1h-benzo{f}indazol-5-yl derivatives as selective glucocorticoid receptor modulators

ABSTRACT

The present invention encompasses compounds of Formula I: (I) or pharmaceutically acceptable salts or hydrates thereof, which are useful as selective glucocorticoid receptor ligands for treating a variety of autoimmune and inflammatory diseases or conditions. Pharamaceutical compositions and methods of use are also included.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US03/10867, filed Apr. 8, 2003, whichclaims priority under 35 U.S.C. 119 to U.S. No. 60/371,948, filed Apr.11, 2002.

BACKGROUND OF THE INVENTION

Intracellular receptors (IR's) are a class of structurally relatedproteins involved in the regulation of gene expression. The steroidhormone receptors are a subset of this superfamily whose natural ligandsare typically comprised of endogenous steroids such as estradiol,progesterone, and cortisol. Man-made ligands to these receptors play animportant role in human health and, of these receptors, theglucocorticoid receptor has an essential role in regulating humanphysiology and immune response. Steroids that interact with theglucocorticoid receptor have been shown to be potent antfinflammatoryagents. The present invention is directed to a novel class of compoundsthat are selective glucocorticoid receptor modulators that have potentani-inflammatory and immunosupresive activity and possess advantagesover steroidal glucocorticoid ligands with respect to side effects,efficacy, toxicity and/or metabolism.

SUMMARY OF THE INVENTION

The present invention encompasses compounds of Formula I:

or pharmaceutically acceptable salts or hydrates thereof, which areuseful as selective glucocorticoid receptor ligands for treating avariety of autoimmune and inflammatory diseases or conditions.Pharamaceutical compositions and methods of use are also included.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a compound represented by Formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

n is 0, 1 or 2;

J is selected from NR¹ or C(R¹)(R²);

K is selected from NR³ or C(R³)(R⁴);

L is selected from NR⁵ or C(R⁵)(R⁶);

X is a bond, —C(O), —N(R¹⁴)—, —N(R¹⁴)—C(O)—, or

-   -   R¹, R⁸ and R¹⁰ are each independently selected from the group        consisting of:

(1) C₁₋₆alkyl,

(2) C₂₋₆alkenyl,

(3) C₃₋₆akynyl,

(4) C₃₋₆cycloalkyl,

(5) C₁₋₆alkoxy,

(6) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,

(7) aryl,

(8) aralkyl,

(9) HET,

(10) —C₁₋₆alkyl-HET,

(11) aryloxy,

(12) aroyloxy,

(13) aralkenyl,

(14) aralkynyl,

(15) hydrogen,

(16) hydroxy and

(17) C₁₋₆alkyl-N(R¹⁴)—S(O)_(k)—, wherein k is 0, 1 or 2,

wherein items (1) to (6) above and the alkyl portions of items (8), (10)and (17) above and the alkenyl portion of item (13) above and thealkynyl portion of item (14) above are optionally substituted from oneup to the maximum number of substitutable positions with a substituentindependently selected from the group consisting of: halo, OR¹³,N(R¹⁴)₂, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)_(k)— and aryl-S(O)_(k)—, whereink is 0, 1 or 2, andwherein items (7), (9), (11) and (12) above and aryl portion of items(8), (13) and (14) above and the HET portion of item (10) above areoptionally substituted from one up to the maximum number ofsubstitutable positions with a substituent independently selected fromthe group consisting of:

-   -   (a) halo,    -   (b) OR¹³,    -   (c) N(R¹⁴)₂,    -   (d) C₁₋₆alkyl,    -   (e) C₂₋₆alkenyl,    -   (f) C₃₋₆akynyl,    -   (g) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (h) aryl,    -   (i) aryl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (j) B ET,    -   (k) aralkyl,    -   (l) aroyl,    -   (m) aryloxy,    -   (n) aralkoxy and    -   (o) CN,        wherein items (d) to (g) above and the alkyl portions of        item (k) above are optionally substituted from one up to the        maximum number of substitutable positions with a substituent        independently selected from the group consisting of: halo, OR¹³        and N(R¹⁴)₂, and        wherein items (h), (i), (j), (l) and (m) above and the aryl        portions of items (k) and (n) above are optionally substituted        from one up to the maximum number of substitutable positions        with a substituent independently selected from the group        consisting of: halo, OR¹³ and C₁₋₄alkyl,        or when X is a bond then R⁸ and R¹⁰ may be joined together to        form a 4- to 8-membered monocylic ring, optionally containing        1-3 heteroatoms selected from O, S and NR¹⁴, and optionally        containing 1 or 2 double bonds;

R², R³, R⁴, R⁵ and R⁶ are each independently selected from the groupconsisting of:

(1) hydrogen,

(2) halo,

(3) C₁₋₆alkyl,

(4) C₂₋₆alkenyl,

(5) C₃₋₆akynyl,

(6) C₃₋₆cycloalkyl,

(7) C₁₋₆alkoxy,

(8) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,

(9) aryl,

(10) aralkyl,

(11) BET and

(12) —C₁₋₆alkyl-HET,

wherein items (3) to (8) above and the alkyl portions of items (10) and(12) above are optionally substituted from one up to the maximum numberof substitutable positions with a substituent independently selectedfrom the group consisting of: halo, OR¹³, N(R¹⁴)₂ andC₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2; andwherein items (9) and (11) and the aryl portion of items (10) and theHET portion of item (12) are optionally substituted from one up to themaximum number of substituable positions with a substituentindependently selected from the group consisting of:

-   -   (a) halo,    -   (b) OR¹³,    -   (c) N(R¹⁴)₂,    -   (d) C₁₋₆alkyl,    -   (e) C₂₋₆alkenyl,    -   (f) C₃₋₆akynyl and    -   (g) C₁₋₆allyl-S(O)_(k)—, wherein k is 0, 1 or 2,        wherein items (d) to (g) above are optionally substituted with        from one up to the maximum number of substitutable positions        with a substituent independently selected from the group        consisting of: halo, OR¹³ and N(R¹⁴)₂,        or R¹ and R³ or R³ and R⁵ may be joined together to form a        double bond;

R⁷ is selected from the group consisting of:

(1) hydrogen,

(2) OR¹³,

(3) C₁₋₄alkyl,

(4) aryl and

(5) aralkyl,

wherein item (3) above and the alkyl portion of item (5) above areoptionally substituted with from one up to the maximum number ofsubstitutable positions with a substituent independently selected fromthe group consisting of: halo, OR¹³ and N(R¹⁴)₂, and

wherein item (4) above and the aryl portion of item (5) above areoptionally substituted with from one up to the maximum number ofsubstitutable positions with a substituent independently selected fromthe group consisting of:

-   -   (a) halo,    -   (b) OR¹³,    -   (c) N(R¹⁴)₂,    -   (d) C₁₋₆alkyl,    -   (e) C₂₋₆alkenyl and    -   (f) C₃₋₆akynyl,        wherein items (d) to (f) above are optionally substituted with        from one up to the maximum number of substitutable positions        with a substituent independently selected from the group        consisting of: halo, OR¹³ and N(R¹⁴)₂;

-   Y is selected from the group consisting of:

(1) hydrogen,

(2) —O—R⁹,

(3) —S(O)_(k)—R⁹, wherein k is 0, 1 or 2,

(4) —C—W—R⁹, wherein W is O or S(O)_(k),

(5) —N(R¹⁵)₂,

(6) —S(O)_(k)—N(R¹⁵)₂,

(7) —N(R¹⁵)—S(O)_(k)—N(R¹⁵)₂,

(8) NO₂,

(9) —C(O)—R¹⁵,

(10) —C(O)O—R¹⁵,

(11) —CN,

(12) halo and

(13) —O—S(O)_(k)—R¹⁵,

R⁹ is selected from the group consisting of: hydrogen, C₁₋₁₂alkyl andaryl, wherein C₁₋₁₂alkyl and aryl are optionally substituted from one upto the maximum number of substituents with halo, or when Y is OR⁹ thenR⁸ and R⁹ may be joined together to form a carbonyl group;

each R¹¹ and R¹² is independently selected from the group consisting of:

(1) halo,

(2) C₁₋₆alkyl,

(3) C₂₋₆alkenyl,

(4) C₁₋₆alkoxy and

(5) hydroxy,

wherein items (2) to (4) above are optionally substituted from one up tothe maximum number of substitutable positions with a substituentindependently selected from the group consisting of: halo, OR¹², N(R¹³)₂and C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2;

each R¹³ and R¹⁴ is independently selected from the group consisting ofhydrogen, C₁₋₄alkyl and C₂₋₄alkenyl, each of said C₁₋₄alkyl andC₂₋₄alkenyl optionally substituted from one up to the maximum number ofsubstitutable positions with a substituent independently selected fromthe group consisting of: halo, C₁₋₄alkoxy, aryl, C₃₋₆cycloalkyl, CN andC₁₋₄alkyl-S(O)_(k), wherein k is 0, 1 or 2;

each R¹⁵ is independently selected from the group consisting of:hydrogen, C₁₋₆alkyl, aryl and C₁₋₁₂alkoxycarbonyl, wherein saidC₁₋₆alkyl and C₁₋₁₂alkoxycarbonyl are optionally substituted from one upto the maximum number of substituable positions with halo and said arylis optionally substituted from one up to the maximum number ofsubstituable positions with halo and C₁₋₄alkyl, optionally substitutedwith 1-3 halo groups; and

HET is a 5- to 10-membered aromatic, partially aromatic or non-aromaticmono- or bicyclic ring, containing 1-4 heteroatoms selected from O, Sand N, and optionally substituted with 1-2 oxo groups.

An embodiment of the invention encompasses a compound of Formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

n is 0, 1 or 2;

J is selected from NR¹ or C(R¹)(R²);

K is selected from NR³ or C(R³)(R⁴);

L is selected from NR⁵ or C(R⁵)(R⁶);

X is a bond, —C(O), —N(R¹⁴)—, —N(R¹⁴)—C(O)— or

R¹, R⁸ and R¹⁰ are each independently selected from the group consistingof:

(1) C₁₋₆alkyl,

(2) C₂₋₆alkenyl,

(3) C₃₋₆akynyl,

(4) C₃₋₆cycloalkyl,

(5) C₁₋₆alkoxy,

(6) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,

(7) aryl,

(8) aralkyl,

(10) —C₁₋₆alkyl-HET,

(11) aryloxy,

(12) aroyloxy,

(13) aralkenyl,

(14) aralkynyl,

(15) hydrogen,

(16) hydroxy and

wherein items (1) to (6) above and the alkyl portions of items (8) and(10) above and the alkenyl portion of item (13) above and the alkynylportion of item (14) above are optionally substituted from one up to themaximum number of substitutable positions with a substituentindependently selected from the group consisting of: halo, OR¹³,N(R¹⁴)₂, C₃₋₆cycloalkyl and C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,andwherein items (7), (9), (11) and (12) above and aryl portion of items(8), (13) and (14) above and the BET portion of item (10) above areoptionally substituted from one up to the maximum number ofsubstitutable positions with a substituent independently selected fromthe group consisting of:

-   -   (a) halo,    -   (b) OR¹³,    -   (c) N(R¹⁴)₂,    -   (d) C₁₋₆alkyl,    -   (e) C₂₋₆alkenyl,    -   (f) C₃₋₆akynyl,    -   (g) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (h) aryl,    -   (i) aryl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (j) HET,    -   (k) aralkyl,    -   (l) aroyl,    -   (m) aryloxy,    -   (n) aralkoxy and    -   (o) CN,        wherein items (d) to (g) above and the alkyl portions of        item (k) above are optionally substituted from one up to the        maximum number of substitutable positions with a substituent        independently selected from the group consisting of: halo, OR¹³        and N(R¹⁴)₂, and        wherein items (h), (i), (j), (l) and (m) above and the aryl        portions of items (k) and (n) above are optionally substituted        from one up to the maximum number of substitutable positions        with a substituent independently selected from the group        consisting of: halo, OR¹³ and C₁₋₄alkyl,        or when X is a bond then R⁸ and R¹⁰ may be joined together to        form a 4- to 8-membered monocylic ring, optionally containing        1-3 heteroatoms selected from O, S and NR¹⁴, and optionally        containing 1 or 2 double bonds;

R², R³, R⁴, R⁵ and R⁶ are each independently selected from the groupconsisting of:

(1) hydrogen,

(2) halo,

(3) C₁₋₆alkyl,

(4) C₂₋₆alkenyl,

(5) C₃₋₆akynyl,

(6) C₃₋₆cycloalkyl,

(7) C₁₋₆alkoxy,

(8) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,

(9) aryl,

(10) aralkyl,

(11) HET and

(12) C₁₋₆alkyl-HET,

wherein items (3) to (8) above and the alkyl portions of items (10) and(12) above are optionally substituted from one up to the maximum numberof substitutable positions with a substituent independently selectedfrom the group consisting of: halo, OR¹³, N(R¹⁴)₂ andC₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2; andwherein items (9) and (11) and the aryl portion of items (10) and theHET portion of item (12) are optionally substituted from one up to themaximum number of substituable positions with a substituentindependently selected from the group consisting of:

-   -   (a) halo,    -   (b) OR¹³,    -   (c) N(R¹⁴)₂,    -   (d) C₁₋₆alkyl,    -   (e) C₂₋₆alkenyl,    -   (f) C₃₋₆akynyl and    -   (g) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,        wherein items (d) to (g) above are optionally substituted with        from one up to the maximum number of substitutable positions        with a substituent independently selected from the group        consisting of: halo, OR¹³ and N(R¹⁴)₂,        or R¹ and R³ or R³ and R⁵ may be joined together to form a        double bond;

R⁷ is selected from the group consisting of:

(1) hydrogen,

(2) OR¹³,

(3) C₁₋₄alkyl,

(4) aryl and

(5) aralkyl,

wherein item (3) above and the alkyl portion of item (5) above areoptionally substituted with from one up to the maximum number ofsubstitutable positions with a substituent independently selected fromthe group consisting of: halo, OR¹³ and N(R¹⁴)₂, and

wherein item (4) above and the aryl portion of item (5) above areoptionally substituted with from one up to the maximum number ofsubstitutable positions with a substituent independently selected fromthe group consisting of:

-   -   (a) halo,    -   (b) OR¹³,    -   (c) N(R¹⁴)₂,    -   (d) C₁₋₆alkyl,    -   (e) C₂₋₆alkenyl and    -   (f) C₃₋₆akynyl,        wherein items (d) to (f) above are optionally substituted with        from one up to the maximum number of substitutable positions        with a substituent independently selected from the group        consisting of: halo, OR¹³ and N(R¹⁴)₂;

-   Y is selected from the group consisting of:

(1) hydrogen,

(2) —O—R⁹,

(3) —S(O)_(k)—R⁹, wherein k is 0, 1 or 2,

(4) —C—W—R⁹, wherein W is O or S(O)_(k),

(5) —N(R¹⁵)₂,

(6) —S(O)_(k)—N(R¹⁵)₂,

(7) —N(R¹⁵)—S(O)_(k)—N(R¹⁵)₂,

(8) NO₂,

(9) —C(O)—R¹⁵,

(10) —C(O)O—R¹⁵,

(11) —CN,

(12) halo and

(13) —O—S(O)_(k)—R¹⁵,

R⁹ is selected from the group consisting of: hydrogen, C₁₋₁₂alkyl andaryl, wherein C₁₋₁₂alkyl and aryl are optionally substituted from one upto the maximum number of substituents with halo, or when Y is OR⁹ thenR⁸ and R⁹ may be joined together to form a carbonyl group;

each R¹¹ and R¹² is independently selected from the group consisting of:

(1) halo,

(2) C₁₋₆alkyl,

(3) C₂₋₆alkenyl,

(4) C₁₋₆alkoxy and

(5) hydroxy,

wherein items (2) to (4) above are optionally substituted from one up tothe maximum number of substitutable positions with a substituentindependently selected from the group consisting of: halo, OR¹², N(R¹³)₂and C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2;

each R¹³ and R¹⁴ is independently selected from the group consisting ofhydrogen and C₁₋₄alkyl, optionally substituted from one up to themaximum number of substitutable positions with halo; and

each R¹⁵ is independently selected from the group consisting of:hydrogen, C₁₋₆alkyl, aryl and C₁₋₁₂alkoxycarbonyl, wherein saidC₁₋₆alkyl and C₁₋₁₂alkoxycarbonyl are optionally substituted from one upto the maximum number of substituable positions with halo and said arylis optionally substituted from one up to the maximum number ofsubstituable positions with halo and C₁₋₄alkyl, optionally substitutedwith 1-3 halo groups.

The optional double bond shown in ring A of the compound of Formula I isdepicted as a dotted line and means that the double bond may or may notbe present as shown below:

The substituent R¹² in Formula I may or may not be present. Whenpresent, one or two R¹² groups may occupy the following positions:

Two R¹² groups may reside on the same carbon atom.

The substituent R¹¹ in Formula I may or may not be present. Whenpresent, one, two or three R¹¹ groups may occupy the followingpositions:

Two R¹¹ groups may reside on the same carbon atom.

The optional double bonds show in ring B of the compound of Formula Imay occupy the following positions:

J, K and L as defined in Formula I mean, for example, the followingstructures:

When X is a bond then R⁸ and R¹⁰ may be joined together to form a 4- to8-membered monocylic ring, optionally containing 1-3 heteroatomsselected from O, S and NR¹⁴, and optionally containing 1 or 2 doublebonds, which means, for example, the following:

These compounds can be made, for example, by following the proceduresoutlined in J. Am. Chem. Soc., vol. 118, 100-110, 1996 and J. Am. ChemSoc., vol. 115, p. 9856-9924, 1993, which are hereby incorporated byreference in their entirety.

When Y is OR⁹ then R⁸ and R⁹ may be joined together to form a carbonylgroup, which means the following:

When X is —N(R¹⁴)—C(O)— the group is attached as follows:

Another embodiment of the invention encompasses a compound of Formula Iwherein:

-   J is NR¹;-   K is NR³;-   L is C(R⁵)(R⁶); and-   R³ and R⁵ are joined together to form a double bond.

Another embodiment of the invention encompasses a compound of Formula Iwherein the optional double bond shown in ring A of the compound ofFormula I is present.

Another embodiment of the invention encompasses a compound of Formula Iwherein R¹ is aryl or BET, said aryl or HET optionally substituted fromone up to the maximum number of substitutable positions with asubstituent independently selected from the group consisting of:

-   -   (a) halo,    -   (b) OR¹³,    -   (c) N(R¹⁴)₂,    -   (d) C₁₋₆alkyl,    -   (e) C₂₋₆alkenyl,    -   (f) C₃₋₆akynyl,    -   (g) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (h) aryl,    -   (i) aryl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (k) aralkyl,    -   (l) aroyl,    -   (m) aryloxy,    -   (n) aralkoxy and    -   (o) CN,        wherein items (d) to (g) above and the alkyl portions of        item (k) are optionally substituted from one up to the maximum        number of substitutable positions with a substituent        independently selected from the group consisting of: halo, OR¹³        and N(R¹⁴)₂, and        wherein items (h), (i), (j), (l) and (m) above and the aryl        portions of items (k) and (n) above are optionally substituted        from one up to the maximum number of substitutable positions        with a substituent independently selected from the group        consisting of: halo, OR¹³ and C₁₋₄alkyl.

Within this embodiment of the invention is encompassed a compound ofFormula I wherein R¹ is phenyl, optionally substituted with 1-3 halogroups.

Another embodiment of the invention encompasses a compound of Formula Iwherein Y is OR⁹. Within this embodiment of the invention is encompasseda compound of Formula I wherein R⁹ is hydrogen.

Another embodiment of the invention encompasses a compound of Formula Iwherein R⁷ is methyl.

Another embodiment of the invention encompasses a compound of Formula Iwherein R⁸ is hydrogen or methyl.

Another embodiment of the invention encompasses a compound of Formula Iwherein X is a bond.

Another embodiment of the invention encompasses a compound of Formula Iwherein R¹⁰ is selected from the group consisting of:

(1) C₁₋₆alkyl,

(2) C₂₋₆alkenyl,

(3) C₃₋₆akynyl,

(4) C₃₋₆cycloalkyl,

(5) C₁₋₆alkoxy,

(6) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,

wherein items (1) to (6) above are optionally substituted from one up tothe maximum number of substitutable positions with a substituentindependently selected from the group consisting of: halo, OR¹³,N(R¹⁴)₂, C₃₋₆cycloalkyl and C₁₋₆alkyl-S(O)_(k), wherein k is 0, 1 or 2.

Another embodiment of the invention encompasses a compound of Formula Iwherein R¹⁰ is selected from the group consisting of:

(1) phenyl

(2) naphthyl,

(3) benzyl,

(4) phenethyl,

(5) phenoxy,

(6) benzoyl and

(7) benzoyloxy,

wherein the aryl portions of items (1) to (7) above are optionallysubstituted from one up to the maximum number of substitutable positionswith a substituent independently selected from the group consisting of:

-   -   (a) halo,    -   (b) OR¹³,    -   (c) N(R¹⁴)₂,    -   (d) C₁₋₆alkyl,    -   (e) C₂₋₆alkenyl,    -   (f) C₃₋₆akynyl,    -   (g) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (h) aryl,    -   (i) aryl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (j) HET,    -   (k) aralkyl,    -   (l) aroyl,    -   (m) aryloxy,    -   (n) aralkoxy and    -   (o) CN,        wherein items (d) to (g) above and the alkyl portions of        item (k) are optionally substituted from one up to the maximum        number of substitutable positions with a substituent        independently selected from the group consisting of: halo, OR¹³        and N(R¹⁴)₂, and        wherein items (h), (i), (j), (l) and (m) above and the aryl        portions of items (k) and (n) above are optionally substituted        from one up to the maximum number of substitutable positions        with a substituent independently selected from the group        consisting of: halo, OR¹³ and C₁₋₄alkyl.

Another embodiment of the invention encompasses a compound of Formula Iwherein R¹⁰ is BET or —C₁₋₄alkyl-BET wherein HET is selected from thegroup consisting of:

(1) pyridine,

(2) thiophene and

(3) furan,

or benzofused analogs of (1) to (3) above.

Another embodiment of the invention encompasses a compound of FormulaII:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

X is a bond;

R⁸ and R¹⁰ are each independently selected from the group consisting of:

(1) C₁₋₆alkyl, optionally substituted with hydroxy,

(2) C₂₋₆alkenyl,

(3) C₃₋₆akynyl,

(4) C₃₋₆cycloalkyl,

(5) phenyl

(6) naphthyl,

(7) benzyl,

(8) phenethyl and

(9) pyridine, thiophene or furan, or benzofused analogs thereof,

and R⁸ is additionally selected from hydrogen,

wherein items (5), (6) and (9) above and aryl portion of items (7) and(8) above and are optionally substituted from one up to the maximumnumber of substitutable positions with a substituent independentlyselected from the group consisting of:

-   -   (a) halo,    -   (b) hydroxy,    -   (c) methoxy,    -   (d) C₁₋₄alkyl,    -   (e) trifluoromethyl,    -   (f) phenoxy,    -   (g) benzyloxy, optionally substituted with methoxy, and    -   (h) CN;

each R¹¹ is independently selected from the group consisting of:

(1) halo,

(2) methyl and

(3) hydroxy; and

R¹⁴ is independently selected from the group consisting of hydrogen andC₁₋₄alkyl.

Another embodiment of the invention encompasses a compound of Formula IIwherein R⁸ is selected from the group consisting of hydrogen orC₁₋₄alkyl.

Another embodiment of the invention encompasses a compound of FormulaIII:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

-   n is 0 or 1,-   R⁸ is hydrogen or methyl,-   R⁹ is hydrogen or methyl or-   R⁸ and R⁹ may be joined together with the oxygen atom shown in    Formula III to form a carbonyl group;-   R¹⁰ is selected from the group consisting of:

(1) phenyl,

(2) naphthyl,

(3) pyridyl,

(4) furyl or benzofuryl,

(5) thienyl or benzothienyl, or the S,S-dioxide thereof,

(6) benzyl,

(7) quinoline,

(8) thiazolyl or benzothiazolyl, and

(9) phenylsulfonylmethyl or phenylsulfonylethyl, wherein

groups (1) to (9) are optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of:

-   -   (a) halo,    -   (b) trifluoromethyl,    -   (c) trifluoromethoxy,    -   (d) —N(R¹⁴), wherein each R¹⁴ is indepedently hydrogen or        C₁₋₄alkyl,    -   (e) pyrrolyl,    -   (f) methoxy, ethoxy or isopropoxy, each optionally substituted        with a substituent selected from: methoxy, benzyl,        cyclopropylmethyl, cyano, methylthio, methylsulfinyl and        methylsulfonyl,    -   (g) methyl,    -   (h) vinyl and    -   (i) hydroxy, and

-   R¹¹ is hydrogen or halo.

Another embodiment of the invention encompasses a compound of FormulaIV:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

-   n is 0 or 1,-   R¹⁰ is selected from the group consisting of:

(1) —CH(OR¹³)-aryl, wherein aryl is phenyl or napthyl,

(2) —CH(OR¹³)-HET, and

(3) —CH(OR¹³)-C₁₋₄alkyl or CH(OR¹³)—C₂₋₄alkenyl, said—CH(OR¹³)—C₁₋₄alkyl or —CH(OR¹³)—C₂₋₄alkenyl optionally substituted withphenylsulfonyl,

-   R¹³ is hydrogen or methyl,-   HET is selected from the group consisting of:

(1) pyridyl,

(2) furyl or benzofuryl,

(3) thienyl or benzothienyl, or the S,S-dioxide thereof,

(4) benzyl,

(5) quinoline,

(6) thiazolyl or benzothiazolyl,

said aryl or HET are optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of:

-   -   (a) halo,    -   (b) trifluoromethyl,    -   (c) trifluoromethoxy,    -   (d) —N(R¹⁴), wherein each R¹⁴ is indepedently hydrogen or        C₁₋₄alkyl,    -   (e) pyrrolyl,    -   (f) methoxy, ethoxy or isopropoxy, each optionally substituted        with a substituent selected from: methoxy, benzyl,        cyclopropylmethyl, cyano, methylthio, methylsulfinyl and        methylsulfonyl,    -   (g) methyl,    -   (h) vinyl and    -   (i) hydroxy, and

-   R¹¹ is hydrogen or halo.

Another embodiment of the invention encompasses a pharmaceuticalcomposition comprising a compound of Formula I in combination with apharmaceutically acceptable carrier.

Another embodiment of the invention encompasses a method for treating aglucocorticoid receptor mediated disease or condition in a mammalianpatient in need of such treatment comprising administering the patient acompoud of Formula I in an amount that is effective for treating theglucocorticoid receptor mediated disease or condition.

Within this embodiment is encompassed the above method wherein theglucocorticoid receptor mediated disease or condition is selected fromthe group consisting of: tissue rejection, leukemias, lymphomas,Cushing's syndrome, acute adrenal insufficiency, congenital adrenalhyperplasia, rheumatic fever, polyarteritis nodosa, granulomatouspolyarteritis, inhibition of myeloid cell lines, immuneproliferation/apoptosis, HPA axis suppression and regulation,hypercortisolemia, stroke and spinal cord injury, hypercalcemia,hypergylcemia, acute adrenal insufficiency, chronic primary adrenalinsufficiency, secondary adrenal insufficiency, congenital adrenalhyperplasia, cerebral edema, thrombocytopenia, Little's syndrome,obesity, metabolic syndrome, inflammatory bowel disease, systemic lupuserythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cellarteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis,hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronicobstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn'sdisease, ulcerative colitis, autoimmune chronic active hepatitis, organtransplantation, hepatitis, cirrhosis, inflammatory scalp alopecia,panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts,atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, buflouspemphigoid, systemic lupus erythematosus, dermatomyositis, herpesgestationis, eosinophilic fasciitis, relapsing polychondritis,inflammatory vasculitis, sarcoidosis, Sweet's disease, type I reactiveleprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis,lichen planus, exfoliative dermatitus, erythema nodosum, acne,hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneousT-cell lymphoma, Human Immunodeficiency Virus (HIV), cell apoptosis,cancer, Kaposi's sarcoma, retinitis pigmentosa, cognitive performance,memory and learning enhancement, depression, addiction, mood disorders,chronic fatigue syndrome, schizophrenia, sleep disorders, and anxiety.

Another embodiment of the invention encompasses a method of selectivelymodulating the activation, repression, agonism and antagonism effects ofthe glucocorticoid receptor in a mammal comprising administering to themammal a compound of Formula I in an amount that is effective tomodulate the glucocorticoid receptor.

The invention is exemplified by the compounds that follow.

The invention is described using the following definitions unlessotherwise indicated.

The term “halogen” or “halo” includes F, Cl, Br, and I.

The term “alkyl” means linear or branched structures and combinationsthereof, having the indicated number of carbon atoms. Thus, for example,C₁₋₆alkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl,butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “alkoxy” means alkoxy groups of a straight, branched or cyclicconfiguration having the indicated number of carbon atoms. C₁₋₆alkoxy,for example, includes methoxy, ethoxy, propoxy, isopropoxy, and thelike.

The term “alkylthio” means alkylthio groups having the indicated numberof carbon atoms of a straight, branched or cyclic configuration.C₁-C₆alkylthio, for example, includes methylthio, propylthio,isopropylthio, and the like.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term “alkynyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon triple bond. C₃₋₆alkynyl, for example, includes,propenyl, 1-methylethenyl, butenyl and the like.

The term “cycloalkyl” means mono-, bi- or tricyclic structures,optionally combined with linear or branched structures, the indicatednumber of carbon atoms. Examples of cycloalkyl groups includecyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl,2-ethyl-1-bicyclo[4.4.0]decyl, and the like.

The term “aryl” is defined as a mono- or bi-cyclic aromatic ring systemand includes, for example, phenyl, naphthyl, and the like.

The term “aralkyl” means an alkyl group as defined above of 1 to 6carbon atoms with an aryl group as defined above substituted for one ofthe alkyl hydrogen atoms, for example, benzyl and the like.

The term “aryloxy” means an aryl group as defined above attached to amolecule by an oxygen atom (aryl-O) and includes, for example, phenoxy,naphthoxy and the like.

The term “aralkoxy” means an aralkyl group as defined above attached toa molecule by an oxygen atom (aralkyl-O) and includes, for example,benzyloxy, and the like.

The term “arylthio” is defined as an aryl group as defined aboveattached to a molecule by an sulfur atom (aryl-S) and includes, forexample, thiophenyoxy, thionaphthoxy and the like.

The term “aroyl” means an aryl group as defined above attached to amolecule by an carbonyl group (aryl-C(O)—) and includes, for example,benzoyl, naphthoyl and the like.

The term “aroyloxy” means an aroyl group as defined above attached to amolecule by an oxygen atom (aroyl-O) and includes, for example,benzoyloxy or benzoxy, naphthoyloxy and the like.

The term “HET” is defined as a 5- to 10-membered aromatic, partiallyaromatic or non-aromatic mono- or bicyclic ring, containing 1-4heteroatoms selected from O, S and N, and optionally substituted with1-2 oxo groups. Preferably, “HET” is a 5- or 6-membered aromatic ornon-aromatic monocyclic ring containing 1-3 heteroatoms selected from O,S and N, for example, pyridine, pyrimidine, pyridazine, furan,thiophene, thiazole, oxazole, isooxazole and the like, or HET is a 9- or10-membered aromatic or partially aromatic bicyclic ring containing 1-3heteroatoms selected from O, S, and N, for example, benzofuran,benzothiophene, indole, pyranopyrrole, benzopyran, quionoline,benzocyclohexyl, naphtyridine and the like. “HET” also includes thefollowing: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl,benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl,furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.

For all of the above definitions, each reference to a group isindependent of all other references to the same group when referred toin the Specification. For example, if both R¹ and R² are HET, thedefinitions of HET are independent of each other and R¹ and R² may bedifferent HET groups, for example furan and thiophene.

The term “treating” encompasses not only treating a patient to relievethe patient of the signs and symptoms of the disease or condition butalso prophylactically treating an asymptomatic patient to prevent theonset of the disease or condition or preventing, slowing or reversingthe progression of the disease or condition. The term “amount effectivefor treating” is intended to mean that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, a system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician. The termalso encompasses the amount of a pharmaceutical drug that will preventor reduce the risk of occurrence of the biological or medical event thatis sought to be prevented in a tissue, a system, animal or human by aresearcher, veterinarian, medical doctor or other clinician.

The following abbreviations have the indicated meanings:

-   -   AIBN=2,2′-azobisisobutyronitrile    -   B.P.=benzoyl peroxide    -   Bn=benzyl    -   CCl₄=carbon tetrachloride    -   D=—O(CH₂)₃O—    -   DAST=diethylamine sulfur trifluoride    -   DCC=dicyclohexyl carbodiimide    -   DCI=1-(3-dimethylaminopropyl)-3-ethyl carbodiimide    -   DEAD=diethyl azodicarboxylate    -   DIBAL=diisobutyl aluminum hydride    -   DME=ethylene glycol dimethylether    -   DMAP=4-(dimethylamino)pyridine    -   DMW=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   Et₃N=triethylamine    -   LDA=lithium diisopropylamide    -   m-CPBA=metachloroperbenzoic acid    -   NBS=N-bromosuccinimide    -   NSAID=non-steroidal anti-inflammatory drug    -   PCC=pyridinium chlorochromate    -   PDC=pyridinium dichromate    -   Ph=phenyl    -   1,2-Ph=1,2-benzenediyl    -   Pyr=pyridinediyl    -   Qn=7-chloroquinolin-2-yl    -   R^(s)=—CH₂SCH₂CH₂Ph    -   r.t.=room temperature    -   rac.=racemic    -   THF=tetrahydrofuran    -   THP=tetrahydropyran-2-yl        Alkyl Group Abbreviations    -   Me=methyl    -   Et=ethyl    -   n-Pr=normal propyl    -   i-Pr=isopropyl    -   n-Bu=normal butyl    -   i-Bu=isobutyl    -   s-Bu=secondary butyl    -   t-Bu=tertiary butyl    -   c-Pr=cyclopropyl    -   c-Bu=cyclobutyl    -   c-Pen=cyclopentyl    -   c-Hex=cyclohexyl

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to comprehend such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium, and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature and the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to avariety of factors including the age, weight, general health, sex, diet,time of administration, rate of excretion, drug combination and responseof the individual patient. In general, the daily dose from about 0.001mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg toabout 10 mg per kg. On the other hand, it may be necessary to usedosages outside these limits in some cases.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for oral administration to humans may contain fromabout 0.5 mg to about 5 g of active agent compounded with an appropriateand convenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain from about 1 mg to about 2 g of an active ingredient,typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg,800 mg, or 1000 mg.

For the treatment of glucocorticoid receptor mediated diseases thecompound of Formula I may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous, intravenous, intramuscular, intrasternalinjection or infusion techniques. In addition to the treatment ofwarm-blooded animals such as mice, rats, horses, cattle, sheep, dogs,cats, etc., the compound of the invention is effective in the treatmentof humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, solutions, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example, magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed withwater-miscible solvents such as propylene glycol, PEGs and ethanol, oran oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Cosolvents suchas ethanol, propylene glycol or polyethylene glycols may also be used.In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ambient temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing a compound of Formula I are employed. (For purposes ofthis application, topical application shall include mouth washes andgargles.) Topical formulations may generally be comprised of apharmaceutical carrier, cosolvent, emulsifier, penetration enhancer,preservative system, and emollient.

The ability of the compounds of Formula I to selectively modulateglucocorticoid receptors makes them useful for treating, preventing orreversing the progression of a variety of inflammatory and autoimmunediseases and conditions. Thus, the compounds of the present inventionare useful to treat, prevent or ameliorate the following diseases orconditions: inflammation, tissue rejection, auto-immunity, variousmalianancies, such as leukemias and lymphomas, Cushing's syndrome, acuteadrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever,polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloidcell lines, immune proliferation/apoptosis, IPA axis suppression andregulation, hypercortisolernia, stroke and spinal cord injury,hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronicprimary adrenal insufficiency, secondary adrenal insufficiency,congenital adrenal hyperplasia, cerebral edema, thrombocytopenia,Little's syndrome, obesity and metabolic syndrome.

The compounds of the present invention are also useful for treating,preventing or reversing the progression of disease states involvingsystemic inflammation such as inflammatory bowel disease, systemic lupuserythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cellarteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis,hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronicobstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn'sdisease, ulcerative colitis, autoimmune chronic active hepatitis, organtransplantation, hepatitis, and cirrhosis.

The compounds of the present invention are useful for treating,preventing or reversing the progression of a variety of topical diseasessuch as inflammatory scalp alopecia, panniculitis, psoriasis, discoidlupus erythematosus, inflamed cysts, atopic dermatitis, pyodermagangrenosum, pemphigus vulgaris, buflous pemphigoid, systemic lupuserythematosus, dermatomyositis, herpes gestationis, eosinophilicfasciitis, relapsing polychondritis, inflammatory vasculitis,sarcoidosis, Sweet's disease, type I reactive leprosy, capillaryhemangiomas, contact dermatitis, atopic dermatitis, lichen planus,exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxicepidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma.

The compounds of the present invention are also useful in treating,preventing or reversing the progression of disease states associatedwith Human Immunodeficiency Virus (HIV), cell apoptosis, and cancerincluding, but not limited to, Kaposi's sarcoma, immune systemactivation and modulation, desensitization of inflammatory responses,IIL-I expression, natural killer cell development, lymphocytic leukemia,and treatment of retinitis pigmentosa. Cogitive and behavioral processesare also susceptible to glucocorticoid therapy where antagonists wouldpotentially be useful in the treatment of processes such as cognitiveperformance, memory and learning enhancement, depression, addiction,mood disorders, chronic fatigue syndrome, schizophrenia, stroke, sleepdisorders, and anxiety.

The invention also encompasses a method for treating a glucocorticoidreceptor mediated disease comprising concomitantly administering to apatient in need of such treatment a compound of Formula I and one oradditional more agents. For treating or preventing asthma or chronicobstructive pulmonary disease, the compounds of Formula I may becombined with one or more agents selected from the group consisting of:β-agonists (e.g., salmeterol), theophylline, anticholinergics (e.g.,atropine and ipratropium bromide), cromolyn, nedocromil and leukotrienemodifiers (e.g., montelukast). For treating or preventing inflammation,the compounds of Formula I may be combined with one or the following: asalicylate, including acetylsalicylic acid, a non-steroidalantiinflammatory drug, including indomethacin, sulindac, mefenamic,meclofenamic, tolfenamic, tolmetin, ketorolac, dicofenac, ibuprofen,naproxen, fenoprofen, ketoprofen, flurbiprofin and oxaprozin, a TNFinhibitor, including etanercept and infliximab, an IL-1 receptorantagonist, a cytotoxic or immunosuppressive drug, includingmethotrexate, leflunomide, azathioprine and cyclosporine, a goldcompound, hydroxychloroquine or sulfasalazine, penicillamine,darbufelone, and a ρ38 kinase inhibitor. The compound of Formula I mayalso be used in combination with bisphonates such as alendronate totreat a glucocorticoid mediated disease and simultaneously inhibitosteoclast-mediated bone resorption.

Methods of Synthesis

Generally, compounds of the present invention may be synthesized byfollowing the following synthetic scheme:

Acid, such as p-toluenesulfonic acid, is added to a solution of theWieland-Miescher ketone i in ethylene glycol to give ketal ii. Ethylformate and sodium hydride are added to ketal ii in an organic solventsuch as anhydrous benzene to afford hydroxyketone iii. The hydroxyketoneiii is dissolved in an appropriate acid such as glacial acetic acid andthe appropriate hydrazine such as p-fluorophenylhyradzine hydroclorideand appropriate base such as sodium acetate is added to give pyrazoleketal iv. The pyrazole ketal iv is dissolved in an aprotic solvent suchas THF and an aqeuous acid such as aqeuous 6N HCl is added to yield theketone v.

Potassium bis(trimethylsilyl amide) is added to(methoxymethyl)triphenylphosponium chloride in an aprotic solvent suchas THF. Ketone v is added to afford compound vi. R¹⁰-Li is added in anaprotic solvent such as THF at low temperature to yield the finalproduct vii.

Methods for making compounds of Formula I outside the scope of formulavii are easily discernible by those having ordinary skill in the art inview of the above method and the examples set for the below. See, forexample, Syth. Commun., 1994, vol. 24, pp. 279-292; Org. Syth., 1985,vol. 63, pp. 37-43; Org. Syth., 1985, vol. 63, pp. 26-36; and Setroids,1963, vol. 2, p. 399.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) all operations were carried out at room or ambient temperature, thatis, at a temperature in the range 18-25° C.,

(ii) evaporation of solvent was carried out using a rotary evaporatorunder reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bathtemperature of up to 60° C.,

(iii) the course of reactions was followed by thin layer chromatography(TLC) and reaction times are given for illustration only;

(iv) melting points are uncorrected and ‘d’ indicates decomposition; themelting points given are those obtained for the materials prepared asdescribed; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(v) the structure and purity of all final products were assured by atleast one of the following techniques: TLC, mass spectrometry, nuclearmagnetic resonance (NMR) spectrometry or microanalytical data;

(vi) yields are given for illustration only;

(vii) when given, NMR data is in the form of delta (δ) values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as internal standard, determined at 500 MHz or600 MHz using the indicated solvent; conventional abbreviations used forsignal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br.broad; etc.: in addition “Ar” signifies an aromatic signal;

(viii) chemical symbols have their usual meanings; the followingabbreviations have also been used v (volume), w (weight), b.p. (boilingpoint), m.p. (melting point), L (litre(s)), mL (millilitres), g(gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq(equivalent(s)).

PREPARATIVE EXAMPLES Ketone A

Step 1:

4 Å molecular sieves (˜5 g) and p-toluenesulfonic acid (5.34 g, 28.05mmol) were added to a solution of the Wieland-Miescher ketone (5 g,28.05 mmol) in ethylene glycol (140 mL). After stirring at roomtemperature for 23 min., the reaction was poured slowly into a 2:1mixture of ice water/sat. aqeuous NaHCO₃ (150 mL). The reaction wasextracted with EtOAc (4×100 mL) and the combined organic layers werewashed with brine (100 mL), dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by flash chromatography (0 to 40%EtOAc/hexanes) on silica gel to afford 5.77 g (93%) of the ketal as awhite solid. LCMS=223; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 5.83 (br d,J=1.8 Hz, 1H), 4.43-3.94 (m, 4H), 2.49-2.40 (m, 3H), 2.39-2.27 (m, 2H),1.95-1.88 (m, 1H), 1.84-1.78 (m, 1H), 1.76-1.64 (m, 3H), 1.37 (s, 3H).

Step 2:

Ethyl formate (7.36 mL, 86.48 mmol) and sodium hydride (60% suspensionin mineral oil; 3.46 g, 86.48 mmol) were added to a cooled solution(−40° C.) of the ketal in anhydrous benzene (200 mL). MeOH (450 μL) wasadded dropwise over 15 min. and the reaction allowed to warm to roomtemperature. After stirring for 3 h, the reaction was cooled to 0° C.and 50 mL H₂O was added. The biphasic system was shaken and the organiclayer was washed with H₂O (3×50 mL). The combined aqueous layers werewashed with diethyl ether (100 mL) and then acidified to pH 5.5-6 withsat. aqueous KH₂PO₄. The aqueous layer was extracted with EtOAc (5×200mL). The combined extracts were dried over Na₂SO₄ and concentrated invacuo to afford 5.04 g (93%) of hydroxyketone product as an orange oil.LCMS=251; (M+1)⁺.

Step 3:

The hydroxyketone (4.1 g, 16.4 mmol) was dissolved in glacial aceticacid (40 mL) and p-fluorophenylhyradzine hydrocloride (2.8 g, 17.22mmol) and sodium acetate (1.41 g, 17.22 mmol) were added. After stirringat room temperature for 2 h, the reaction was poured slowly into 10%NaHCO₃ (1 L) and extracted with EtOAc (6×500 mL). The combined extractswere washed with brine (500 mL), dried over MgSO₄ and concentrated invacuo. The crude material was purified by flash chromatography (10%EtOAc/hexanes) on silica gel to afford 2.26 g (41%) of the pyrazoleketal as an orange solid. LCMS=421; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ7.47-7.44 (m, 2H), 7.43 (s, 1H), 7.18-7.16 (d, J=8.5 Hz, 1H), 7.16-7.14(d, J=8.7 Hz, 1H), 6.22 (br d, J=2.2 Hz, 1H), 4.11-4.01 (m, 4H),3.20-3.16 (d, J=15.7 Hz, 1H), 2.54-2.51 (d, J=16 Hz, 1H), 2.51-2.40 (m,1H), 2.34-2.28 (m, 1H), 1.88-1.64 (m, 4H), 1.23 (s, 3H).

Step 4:

The pyrazole ketal (2.26 g; 6.65 mmol) was dissolved in THF (65 mL) and6N HCl (4.43 mL, 26.6 mL) was added. The reaction was heated at 65° C.for 3.5 h and then poured slowly into 10% NaHCO₃ (150 mL). The mixturewas extracted with EtOAc (4×250 mL) and the combined extracts washedwith brine (2×200 mL), dried over MgSO₄ and concentrated in vacuo toafford 1.97 g (100%) of Ketone A as a brown oil. LCMS=297; (M+1)⁺. ¹HNMR (CDCl₃, 500 MHz): δ 7.50 (s, 1H), 7.49-7.45 (m, 2H), 7.20-7.16 (m,2H), 6.31 (br d, J=2 Hz, 1H), 2.96-2.88 (m, 2H), 2.72-2.62 (m, 2H),2.59-2.53 (m, 2H), 2.14-2.08 (m, 1H), 1.75-1,64 (qt, J=13.1 Hz, J=4.3Hz, 1H), 1.27 (s, 3H).

Aldehyde B

Step 1: Preparation of Aldehyde B

A suspension of (methoxymethyl)triphenylphosponium chloride (4.17 g,12.16 mmol) in THF (40 mL) was cooled to −40° C. Potassiumbis(trimethylsilyl amide) (20.3 mL of a 0.5 M solution in toluene, 10.15mmol) was added dropwise by syringe and the reaction was allowed to warmto 0° C. and held at that temperature for 15 min. A solution of ketone A(1.2 g, 4.05 mmol) in THF (12 mL) was added and the reaction was allowedto warm to room temperature. After stirring at room temperature for 24h, 10 mL of a 1:1 solution of TBF/MeOH was added to the reactionfollowed by 10 mL of 4 N HCl. The reaction became biphasic and stirringwas continued at room temperature. After 36 h, the reaction was dilutedwith EtOAc (300 mL) and washed with H₂O, saturated NaHCO₃, and brine (50mL each). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(5 to 25% EtOAc/hexanes) on silica gel to afford 939.7 mg (75%) of theproduct B as a tan solid; 8:1 (β:α) mixture of aldehyde diastereomers.R_(f)=0.19 (25% EtOAc/hexanes). LCMS=311; (M+1)⁺. ¹H NMR (major isomer)(CDCl₃, 500 MHz) δ 9.91 (d, J=1.8 Hz, 1H), 7.43-7.46 (m, 3H), 7.16 (t,J=8.6 Hz, 2H), 6.17 (d, J=1.9 Hz, 1H), 3.11 (d, J=15.6 Hz, 1H), 2.91 (d,J=15.6 Hz, 1H), 2.32-2.45 (m, 3H), 1.87-1.98 (m, 2H), 1.75 (m, 1H), 1.43(m, 1H), 1.12 (s, 3H).

Ketone C was prepared in the same manner as ketone A.

Aldehyde F

Step 1:

A suspension of methyltriphenylphosphonium bromide (2.05 g, 5.75 mmol)in THF (25 mL) was cooled to −40° C. Potassium bis(trimethylsilyl amide)(9.2 mL of a 0.5 M solution in toluene, 4.6 mmol) was added dropwise bysyringe and the reaction was allowed to warm to 0° C. and held at thattemperature for 15 minutes. Next, a solution of ketone C (323.7 mg, 1.15mmol) in THF (5 mL) was added by cannula. The reaction was allowed towarm to room temperature. After stirring at room temperature for 2hours, the reaction was filtered through a plug of silica gel with 50%EtOAc/hexanes. The filtrate was concentrated and the residue waspurified by flash chromatography with 15% EtOAc/hexanes to afford 265.2mg (83%) of D. R_(f)=0.39 (25% EtOAc/hexanes). LCMS=281; (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz) δ 7.46-7.49 (m, 2H), 7.44 (s, 1H), 7.13-7.17 (m, 2H),6.19 (s, 1H), 4.95 (s, 1H), 4.86 (s, 1H), 2.81 (d, J=15.3 Hz, 1H), 2.73(m, 1H), 2.69 (d, J=15.6 Hz, 1H), 2.54-2.67 (m, 2H), 2.48 (m, 1H), 1.17(s, 3H).

Step 2:

To a solution of D (265.2 mg, 0.947 mmol) in TBF (17 mL) was added 9-BBN(5.7 mL of a 0.5 M solution in TBF, 2.84 mmol). The reaction was stirredat room temperature for 1.5 hours and then cooled to 0° C. EtOH (6.8mL), 6N NaOH (2.25 mL) and 30% H₂O₂ (1.2 mL) were added, the ice bathwas removed, and the reaction was heated to 50° C. for 1 hour. Thereaction was then cooled to room temperature, diluted with EtOAc (100mL), and washed with H₂O and brine (50 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo.

The residue was purified by flash chromatography with 60% EtOAc/hexanesto afford 282.2 mg (100%) of E. R_(f)=0.19 (55% EtOAc/hexanes).LCMS=299; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.46-7.48 (m, 2H), 7.41 (s,1H), 7.13-7.16 (m, 2H), 6.14 (s, 1H), 3.81 (dd, J=10.6, 7.1 Hz, 1H),3.75 (dd, J=10.8, 7.0 Hz, 1H), 2.92 (d, J=15.3 Hz, 1H), 2.66 (d, J=15.3Hz, 1H), 2.63 (m, 1H), 2.47 (m, 1H), 2.10 (m, 1H), 2.03 (m, 1H), 1.58(m, 1H), 0.97 (s, 3H).

Step 3:

To a solution of oxalyl chloride (46 μL, 0.524 mmol) in CH₂Cl₂ (2 mL) at−78° C. was added DMSO (75 μL, 1.05 mmol) in CH₂Cl₂ (1 mL). The reactionwas stirred at −78° C. for 5 minutes and then alcohol E (52.1 mg, 0.175mmol) in CH₂Cl₂ (2 mL) was added. The reaction was stirred for 15minutes and then Et₃N (295 μL, 2.1 mmol) was added. The reaction waswarmed to room temperature, stirred for 20 minutes, and diluted withEtOAc (50 mL). The organic solution was washed with H₂O, saturatedNaHCO₃, brine, 1N HCl, saturated NaHCO₃, and brine (15 mL each). Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by flash chromatography (40% EtOAc/hexanes) toafford 41.5 mg (80%) of F as a clear oil. R_(f)=0.27 (40%EtOAc/hexanes). LCMS=297; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 9.89 (d,J=1.6 Hz, 1H), 7.43-7.46 (m, 2H), 7.42 (s, 1H), 7.13-7.16 (m, 2H), 6.17(s, 1H), 3.01 (d, J=15.4 Hz, 1H), 2.88 (d, J=15.4 Hz, 1H), 2.67-2.75 (m,2H), 2.51 (m, 1H), 2.56 (m, 1H), 2.06 (m, 1H), 1.06 (s, 3H).

EXAMPLES Example 1

Step 1: Addition of Aryl Grignard Reagents to Aldehyde B

Aldehyde B (42.7 mg, 0.138 mmol) was dissolved in TBF (4 mL) and cooledto 0° C. 4-fluorobenzyl magnesium chloride (5.5 mL of a 0.25 M solutionin Et₂O, 1.38 mmol) was added dropwise by syringe. The reaction wasstirred at 0° C. for 1 h and then quenched with saturated NH₄Cl (25 mL).The mixture was extracted with EtOAc (100 mL) and the organic layer waswashed with H₂O and brine (25 mL each), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The major product was isolated by flashchromatography (5 to 25% EtOAc/hexanes) to afford 40.6 mg (70%) ofExample 1 as a single diastereomer. R_(f)=0.11 (25% EtOAc/hexanes).LCMS=421; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.42-7.44 (m, 2H), 7.38 (s,1H), 7.13-7.20 (m, 4H), 7.02 (t, J=8.6 Hz, 2H), 6.09 (d, J=2.3 Hz, 1H),4.16 (br s, 1H), 2.85-2.90 (m, 2H), 2.68 (dd, J=13.5, 5.7 Hz, 1H), 2.41(m, 1H), 2.26-2.32 (m, 2H), 1.95 (m, 1H), 1.80 (m, 1H), 1.71 (qd,J=13.0, 3.3 Hz, 1H), 1.56 (dd, J=12.5, 3.5 Hz, 1H), 1.40 (m, 1H), 1.12(s, 3H).

The following compounds are synthesized following procedures analogousto that described in Example 1:

Compound Molecular structure LCMS (M + 1)⁺ 2

481 3

449 4

353 5

367 6

433 7

417 8

459 9

433 10

433 11

463 12

421 13

417 14

421 15

417 16

367 17

439 18

472 19

431 20

431 21

351 22

403 23

403 24

353 25

381 26

457 27

417 28

443 29

461 30

417 31

419

Example 32

Step 1: Addition of Aryl or Vinyl Lithium Reagents to Aldehyde B

A solution of 1-bromo-4-fluorobenzene (176 μL, 1.6 mmol) in Et₂O (16 mL)was cooled to −78° C. and tBuLi (1.9 mL of a 1.7 M solution in pentanes,3.2 mmol) was added dropwise by syringe. The reaction was stirred at−78° C. for 20 min. and then aldehyde B (49.6 mg, 0.16 mmol) in TBF (4mL) was added by cannula. The reaction was stirred at −78° C. for 45min. 1 mL of isopropyl alcohol was added at −78° C. and the reaction waspoured into saturated NH₄Cl. The mixture was extracted with EtOAc (100mL) and the organic layer was washed with water and brine (25 mL each).The organic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by flash chromatography (5 to 20% EtOAc/hexanes)gave 52.8 mg of Example 32 contaminated with minor diastereomers.Further purification by chiral HPLC (AD column, 20% isopropylalcohol/heptanes) gave 35.6 mg (55%) of pure Example 32. R_(f)=0.16 (25%EtOAc/hexanes). LCMS=407; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.45 (m,4H), 7.32 (dd, J=9.5, 5.0 Hz, 2H), 7.15 (t, J=8.5 Hz, 211), 7.04 (t,J=8.8 Hz, 2H), 6.12 (d, J=2.1 Hz, 1H), 5.18 (s, 1H), 3.18 (d, J=15.1 Hz,1H), 2.75 (d, J=15.1 Hz, 1H), 2.41 (m, 1H), 2.28 (bd, J=15.1 Hz, 1H),1.82 (m, 1H), 1.66-1.71 (m, 2H), 1.58 (m, 1H), 1.26 (s, 3H), 1.20 (m,1H).

The following compounds were synthesized following procedures analogousto that described in Example 32:

Com- LCMS pound Molecular structure (M + 1)⁺ 33

407 34

390 35

389 36

390 37

437 38

390 39

445 40

425 41

457 42

395 43

415 44

437 45

439 46

439 47

379 48

421 49

433 50

441 51

423 52

543 53

408 54

473 55

450 56

472 57

455 58

469 59

435 60

475 61

433 62

457 63

463

Example 64

Step 1: Oxidation to the ketone.

A solution of Example 32 (23.0 mg, 0.057 mmol) in CH₂Cl₂ (2 mL) wascooled to 0° C. and NMO (10 mg, 0.085 mmol) was added. After 5 minutes,TPAP (2 mg, 0.0057 mmol) was added to the reaction. The reaction wasstirred at 0° C. for 3 hours and then loaded directly onto a column ofsilica gel. Elution with 100% CH₂Cl₂ followed by 25% EtOAc/hexanesafforded 19.2 mg (84%) of product G. R_(f)=0.32 (25% EtOAc/hexanes).LCMS=405; (M+1)⁺.

Step 2: Reduction of ketone.

Compound G (19.2 mg, 0.048 mmol) was dissolved in MeOH (2 mL) and cooledto 0° C. NaBH₄ (10 mg 0.238 mmol) was added. The reaction was stirred at0° C. for 15 min. and then quenched with saturated NH₄Cl (5 mL). Themixture was extracted with EtOAc (30 mL). The organic layer was washedwith H₂O and brine (10 mL each), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash chromatography(40% EtOAc/hexanes) followed by chiral HPLC to remove minor impurities(AD column, 12% IPA/hexanes) to give 12.6 mg (65%) of pure Example 64.R_(f)=0.16 (25% EtOAc/heptanes). LCMS=407; (M+1)⁺.

¹H NMR (CDCl₃, 600 MHz): δ 7.45 (dd, J=9.0, 4.8 Hz, 2H), 7.40 (s, 1H),7.32 (dd, J=8.4, 5.4 Hz, 2H), 7.14 (t, J=8.4 Hz, 2H), 7.04 (t, J=8.4 Hz,2H), 6.15 (s, 1H), 4.64 (d, J=9.0 Hz, 1H), 3.63 (d, J=16.2 Hz, 1H), 2.78(d, J=16.2 Hz, 1H), 2.27-2.29 (m, 2H), 2.07 (bs, 1H), 1.89 (m, 1H), 1.68(m, 1H), 1.05-1.25 (m, 2H), 1.13 (s, 3H).

The following examples were synthesized following a procedure analogousto that described in Example 64:

Com- pound Molecular structure LCMS (M + 1)⁺ 65

390 66

369 67

408 68

445

Example 69

Step 1: Addition of Aryl Lithium to Aldehyde B.

A solution of O-triisopropylsilyloxy-3-bromobenzyl alcohol (230 mg, 0.67mmol) in Et₂O (6.5 mL) was cooled to −78° C. and t-BuLi (785 μL of a 1.7M solution in pentanes, 1.34 mmol) was added. The reaction was stirredat −78° C. for 15 min. Aldehyde B (20.7 mg, 0.067 mmol) was added bycannula as a solution in TBF (2 mL). The reaction was stirred at −78° C.for 30 min. 1 mL of isopropyl alcohol was added and the reaction waspoured into saturated NH₄Cl (15 mL). The mixture was extracted withEtOAc (50 mL). The organic layer was washed with H₂O and brine (15 mLeach), dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography (silica gel, 5 to 15%EtOAc/hexanes) to give 32.4 mg of product containing 1 major and 2 minordiastereomers. Further purification by chiral HPLC (AD column, 15%IPA/heptanes) afforded 19.4 mg (51%) of pure H (major diastereomer).R_(f)=0.22 (25% EtOAc/hexanes). LCMS=575; (M+1)⁺. ¹H NMR (CDCl₃, 500MHz): δ 7.45-7.48 (m, 3H), 7.36 (s, 11), 7.33 (t, J=7.6 Hz, 1H), 7.24(t, J=6.8 Hz, 2H), 7.13-7.17 (m, 2H), 6.11 (d, J=2.0 Hz, 1H), 5.19 (s,1H), 4.86 (s, 2H), 3.19 (d, J=15.1 Hz, 1H), 2.76 (d, J=15.1 Hz, 1H),2.41 (m, 1H), 2.27 (br d, J=15.1 Hz, 1H), 1.63-1.82 (m, 5H), 1.27 (s,3H), 1.15-1.22 (m, 3H), 1.10 (d, J=6.9 Hz, 18H).

Step 2: Desilyation of the Protected Alcohol or Phenol

Compound H (19.4 mg, 0.034 mmol) was dissolved in THF (3 mL) and cooledto 0° C. TBAF (169 μL of a 1 M solution it THF, 0.169 mmol) was added.The reaction was stirred at 0° C. for 20 min. and then quenched withsaturated NH₄Cl (5 mL). The mixture was extracted with EtOAc (30 mL).The organic layer was washed with H₂O and brine (10 mL each), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byflash chromatography (75% EtOAc/hexanes) to give 12.9 mg (91%) of pureExample 69. R_(f)=0.28 (75% EtOAc/hexanes). LCMS=419; (M+1)⁺. ¹H NMR(DMSO, 500 MHz): δ 7.50-7.53 (m, 3H), 7.34 (t, J=8.8 Hz, 2H), 7.29 (s,1H), 7.25 (t, J=7.4 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.3 Hz,1H), 6.17 (s, 1H), 5.12 (t, J=5.8 Hz, 1H), 4.99-5.03 (m, 2H), 4.48 (d,J=5.7 Hz, 2H), 3.19 (d, J=15.3 Hz, 1H), 2.73 (d, J=15.3 Hz, 1H),2.26-2.36 (m, 2H), 1.63-1.71 (m, 2H), 1.53 (d, J=11.2 Hz, 1H), 1.38 (d,J=12.8 Hz, 1H), 1.17 (s, 3H), 1.03 (m, 1H).

The following examples were synthesized following a procedure analogousto that described in Example 69:

Com- LCMS pound Molecular structure (M + 1)⁺ 70

405 71

441 72

405 73

405

Example 74

Step 1: Alkylation of Example 73.

Example 73 (10.5 mg, 0.025 mmol) and Cs₂CO₃ (32.4 mg, 0.100 mmol) werecombined in a 10 mL flask and DMF (1 mL) was added. Allyl iodide (5 μL,0.055 mmol) was added and the reaction was stirred at room temperaturefor 1 hour. Next, the reaction was poured into H₂O (5 mL) and theaqueous solution was extracted with EtOAc (25 mL). The organic layer waswashed with brine (5 mL), dried over Na₂SO₄, filtered, and concentratedin vacuo. Purification of the residue by flash chromatography (40%EtOAc/hexanes) afforded 11.4 mg (99%) of Example 74. R_(f)=0.25 (40%EtOAc/hexanes). LCMS=463; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.44-7.47(m, 3H), 7.16 (t, J=8.5 Hz, 2H), 7.05 (dd, J=11.0, 8.0 Hz, 1H), 6.99(dd, J=8.5, 2.0 Hz, 1H), 6.85 (m, 1H), 6.11 (d, J=1.5 Hz, 1H), 6.07 (m,1H), 5.43 (dd, J=17.5, 1.5 Hz, 1H), 5.31 (dd, J=10.5, 1.0 Hz, 1H), 5.13(s, 1H), 4.63 (d, J=4.5 Hz, 1H), 3.17 (d, J=15.0 Hz, 1H), 2.73 (d,J=15.0 Hz, 1H), 2.40 (m, 1H), 2.28 (d, J=15.0 Hz, 1H), 1.58-1.83 (m,4H), 1.25 (s, 3H), 1.21 (m, 1H).

The following examples were synthesized following a procedure analogousto that described in Example 74:

Com- LCMS pound Molecular structure (M + 1)⁺ 75

451 76

465 77

481 78

513 79

477 80

462 81

483

Example 82

Step 1:

Aldehyde B (105.5 mg, 0.34 mmol) was dissolved in CH₂Cl₂ (8 mL) andN,N-diisopropylethylamine (1.42 mL, 8.16 mmol) was added followed byTESOTf (1.08 mL, 4.08 mmol). The reaction was stirred at roomtemperature for 6 h, quenched with 1 mL of isopropyl alcohol and dilutedwith EtOAc (50 mL). The organic solution was washed with saturatedNaHCO₃ and brine (10 mL each), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash chromatography(15% EtOAc/hexanes) to afford I which was used directly in the nextreaction without further characterization.

Step 2:

I was dissolved in CH₂Cl₂ (5 mL) and N-fluorobenzenesulfonimide (536 mg,1.7 mmol) was added. The reaction was stirred at room temperature for 15h and then concentrated. The residue was purified by flashchromatography (5 to 15% EtOAc/hexanes) to afford 52.1 mg (47%) of twoseparable diastereomers, 19.5 mg (18%) of the less polar diastereomer Jand 32.6 mg (29%) of the more polar diastereomer K.

Less polar diastereomer J: R_(f)=0.24 (50/42/8 hexanes/CH₂Cl₂/TIME).LCMS=329; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 9.88 (d, J=7.1 Hz, 1H),7.42-7.45 (m, 2H), 7.37 (s, 1H), 7.14-7.18 (m, 2H), 6.25 (s, 1H), 2.89(d, J=16 Hz, 1H), 2.78 (d, J=16 Hz, 1H), 2.53 (m, 1H), 2.33 (br d, J=14Hz, 1H), 2.06 (m, 1H), 1.97 (m, 1H), 1.83 (m, 1H), 1.69 (m, 1H), 1.32(d, J=1.4 Hz, 3H).

More polar diastereomer K: R_(f)=0.21 (50/42/8 hexanes/CH₂Cl₂/TBME).LCMS=329; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 9.91 (d, J=5.7 Hz, 1H),7.42-7.45 (m, 3H), 7.16 (t, J=8.6 Hz, 2H), 6.27 (d, J=2.1 Hz, 1H), 3.51(d, J=15.3 Hz, 1H), 2.44-2.52 (m, 2H), 2.39 (br d, J=15.8 Hz, 1H), 2.10(m, 1H), 1.76-1.90 (m, 2H), 1.30 (m, 1H), 1.18 (s, 3H).

Step 3:

Fluoroaldehyde diastereomer J (17.6 mg, 0.054 mmol) was dissolved in THF(2 mL) and cooled to −78° C. BnMgCl (536 μL of a 1 M solution in Et₂O,0.536 mmol) was added dropwise by syringe. The reaction was warmed to 0°C. for 10 min and then quenched with isopropyl alcohol (500 μL) andpoured into saturated NH₄Cl (10 mL). The mixture was extracted withEtOAc (50 mL). The organic layer was washed with H₂O and brine (15 mLeach), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography (5 to 15% EtOAc/hexanes) togive 5.3 mg (24%) of a less polar diastereomer of Example 82 and 3.8 mg(17%) of a more polar diastereomer of Example 82.

Less polar diastereomer of Example 82: R_(f)=0.40 (25% EtOAc/hexanes, 2elutions). LCMS=421; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.41-7.44 (m,2H), 7.38 (s, 1H), 7.31-7.34 (m, 2H), 7.24-7.26 (m, 3H), 7.12-7.16 (m,2H), 6.14 (s, 1H), 4.21 (t, J=9.5 Hz, 1H), 3.19 (d, J=16.0 Hz, 1H), 3.11(d, J=13.3 Hz, 1H), 7.75 (dd, J=13.5, 10.5 Hz, 1H), 2.67 (d, J=16.0 Hz,1H), 2.61 (m, 1H), 2.30 (m, 1H), 2.16 (m, 1H), 1.97-2.12 (m, 2H), 1.81(m, 1H), 1.26 (d, J=2.5 Hz, 3H).

More polar diastereomer of Example 82: R_(f)=0.37 (25% EtOAc/hexanes, 2elutions). LCMS=421; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.45 (dd, J=8.5,4.8 Hz, 2H), 7.42 (s, 3H), 7.33 (t, J=7.4 Hz, 2H), 7.14-7.18 (m, 3H),6.18 (s, 1H), 4.05 (dd, J=21, 10.5 Hz, 1H), 3.12 (d, J=13.5 Hz, 1H),2.97 (s, 2H), 2.78 (dd, J=13.5, 10.4 Hz, 1H), 2.69 (m, 1H), 2.24 (m,1H), 1.89-2.05 (m, 3H), 1.79 (br s, 1H), 1.67 (m, 1H), 1.35 (d, J=3 Hz,1H).

The two other possible diastereomers of 82 were prepared in similarmanner from the more polar fluoroaldehyde diastereomer K.

Example 83 and 84

Step 1: Addition of Grignard Reagents to Fluoroaldehyde K

Fluoroaldehyde K (28.7 mg, 0.0875 mmol) was dissolved in THF (6 mL) andcooled to 0° C. 4-fluorobenzyl magnesium bromide (218 μL of a 2.0 Msolution in diethyl ether, 0.438 mmol) was added dropwise by syringe.The reaction was stirred at 0° C. for 1 hour and then quenched withsaturated NH₄Cl (10 mL). The mixture was extracted with EtOAc (40 mL)and the organic layer was washed with H₂O and brine (10 mL each), driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification by flashchromatography (5 to 80% EtOAc/hexanes) yielded a mixture of 2diastereomers. Further purification by PILC (40/40/20hexanes/CH₂Cl₂/Et₂O) afforded 18.4 mg (50%) of the less polardiastereomer and 11.1 mg (30%) of the more polar diastereomer.

Less Polar diastereomer: R_(f)=0.20 (25% EtOAc/hexanes). LCMS=425;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.43 (m, 2H), 7.40 (s, 1H), 7.36 (t,J=6 Hz, 2H), 7.13 (t, J=8.4 Hz, 2H), 7.05 (t, J=9 Hz, 2H), 6.17 (s, 1H),5.20 (s, 1H), 3.36 (d, J=15 Hz, 1H), 2.81 (s, 1H), 2.77 (d, J=15 Hz,1H), 2.47 (m, 1H), 2.29 (m, 1H), 2.15 (m, 1H), 1.82 (m, 1H), 1.57 (m,2H), 1.33 (s, 3H).

More Polar diastereomer: R_(f)=0.20 (25% EtOAc/hexanes). LCMS=425;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.43-7.36 (m, 5H), 7.13 (t, J=8.4 Hz,2H), 7.05 (t, J=9 Hz, 2H), 6.18 (s, 1H), 4.93 (d, J=15.5 Hz, 1H), 3.42(d, J=16 Hz, 1H), 3.12 (d, J=16 Hz, 1H), 2.52 (m, 1H), 2.36 (m, 1H),1.90 (m, 1H), 1.66 (m, 1H), 1.03 (s, 3H).

Example 84 and 85

Step 1: Addition of Aryl Lithium to Fluoroaldehyde K.

4-bromopyridine HCl (257.9 mg, 1.33 mmol) was dissolved in 5% Na₂CO₃ (8mL). The solution was then extracted with Et₂O (12 mL) and the Et₂Olayer was dried over Mg₂SO₄, filtered, and concentrated to dryness. Theresidue was azeotroped with benzene (1 mL) and was then dissolved inEt₂O (11.2 ml) and cooled to −78° C. t-BuLi (527 μL of a 1.7 M solutionin pentanes, 0.973 mmol) was added dropwise by syringe. The reaction wasstirred at −78° C. for 20 minutes and then fluoroaldehyde K (29.0 mg,0.088 mmol) in THF (3 mL) was added by cannula. The reaction was stirredat −78° C. for 45 minutes. 1 mL of isopropyl alcohol was added at −78°C. and then the reaction was poured into saturated NH₄Cl (10 mL). Themixture was extracted with EtOAc (50 mL) and the organic layer waswashed with water and brine (15 mL each). The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification by flashchromatography (20 to 100% EtOAc/hexanes) yielded a mixture of 2diastereomers. Further purification using an AD chiral column (25%IPA/heptanes) afforded 19.1 mg (53%) of peak 1 and 4.8 mg (13%) of peak2.

Peak 1: R_(f)=0.50 (100% EtOAc). LCMS=408; (M+1)⁺. ¹H NMR (CDCl₃, 600MHz): δ 8.42 (s, 2H), 7.40 (m, 2H), 7.36 (s, 1H), 7.34 (m, 2H), 7.12 (t,J=8.4 Hz, 2H), 6.16 (s, 1H), 3.37 (d, J=16 Hz, 1H), 2.77 (d, J=16 Hz,1H), 2.46 (m, 1H), 2.20 (m, 2H), 1.52 (m, 3H), 1.18 (s, 3H).

Peak 2: R_(f)=0.50 (100% EtOAc). LCMS=408; (M+1)⁺. ¹H NMR (CDCl₃, 600MHz): δ 8.63 (s, 2H), 7.42 (m, 2H), 7.36 (m, 2H), 7.26 (s, 1H), 7.15 (t,J=8.4 Hz, 2H), 6.29 (s, 1H), 4.92 (d, J=18.6 Hz, 1H), 3.43 (d, J=16 Hz,1H), 3.13 (d, J=15.6 Hz, 1H), 2.36 (m, 2H), 1.69 (m, 1H), 1.65 (m, 2H),1.12 (s, 3H).

The following compound was synthesized following procedures analogous tothose described for fluoroaldehyde K and beginning from aldehyde F:

Com- LCMS pound Molecular structure (M + 1)⁺ L

315

Example 86

Step 1: Addition of Aryl Lithium to Fluoroaldehyde L.

A solution of 3-Bromothianapthene (113.3 μL, 0.866 mmol) in Et₂O (8 mL)was cooled to −78° C. and t-BuLi (1.01 mL of a 1.7 M solution inpentanes, 1.73 mmol) was added dropwise by syringe. The reaction wasstirred at −78° C. for 20 minutes and then fluoroaldehyde L (27.2 mg,0.0866 mmol) in TBF (2 mL) was added by cannula. The reaction wasstirred at −78° C. for 45 minutes. 1 mL of isopropyl alcohol was addedat −78° C. and then the reaction was poured into saturated NH₄Cl (10mL). The mixture was extracted with EtOAc (50 mL) and the organic layerwas washed with water and brine (15 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo. Purification byflash chromatography (5 to 20% EtOAc/hexanes) followed by PTLC (20/40/40hexanes/CH₂Cl₂/Et₂O) followed by an AD chiral column (25% IPA/heptanes)afforded 1.6 mg (4%) of example 86: R_(f)=0.43 (60% EtOAc/hexanes).LCMS=449; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.95 (d, J=7.8 Hz, 1H),7.90 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.42 (m, 4H), 7.15 (t, J=8.4 Hz,2H), 6.27 (s, 1H), 5.38 (dd, J=5.4 Hz, 22.2 Hz, 1H), 3.38 (d, J=16.2 Hz,1H), 3.06 (d, J=16.2 Hz, 1H), 2.58 (m, 2H), 2.04 (m, 1H), 1.73 (m, 1H),1.36 (s, 3H).

Example 87

Step 1:

Aldehyde B (19.7 mg, 0.0635 mmol) was dissolved in MeOH (2 mL), and thesolution was cooled to 0° C. NaBH₄ (12 mg, 0.317 mmol) was added and thereaction was stirred at 0° C. for 30 min. 1 mL of saturated NH₄Cl wasadded to quench the reaction, and the mixture was extracted with EtOAc(25 mL). The organic layer was washed with H₂O and brine (10 mL each),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography (5 to 30% EtOAc/hexanes) to afford 13.2mg (67%) of 87 as a white solid (9:1 ratio of diastereomers). R_(f)=0.13(25% EtOAc/hexanes). LCMS=313; (M+1)⁺. ¹H NMR (major diastereomer)(CDCl₃, 500 MH) δ 7.43-7.47 (m, 2H), 7.40 (s, 1H), 7.15 (t, J=8.5 Hz,1H), 6.12 (d, J=1.9 Hz, 1H), 3.91 (dd, J=10.5, 3.9 Hz, 1H), 3.51 (dd,J=10.0, 8.9 Hz, 1H), 2.96 (d, J=15.5 Hz, 1H), 2.66 (d, J=15.5 Hz, 1H),2.30-2.42 (m, 2H), 2.02 (m, 1H), 1.89 (m, 1H), 1.66 (m, 1H), 1.34-1.45(m, 2H), 0.95 (s, 3H).

Example 88

Step 1

Example 22 (9.5 mg, 0.0236 mmol) was dissolved in CH₂Cl₂ (1 mL) and PCC(15.2 mg, 0.0708 mmol) was added. The reaction was stirred at roomtemperature for 1 hr and then diluted with hexanes (2 mL) and filteredthrough a plug of silica gel with 40% EtOAc/hexanes. The filtrate wasconcentrated and the residue was purified by preparatory thin layerchromatography (25% EtOAc/hexanes) to afford 5.0 mg (53%) of Example 88as a white solid. R_(f)=0.27 (25% EtOAc/hexanes). LCMS=401; (M+1)⁺. ¹HNMR (CDCl₃, 500 MHz) δ 7.42-7.45 (m, 1H), 7.37 (s, 1H), 7.35 (t, J=7.4Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.22 (d, J=7.1 Hz, 1H), 7.13-7.22 (m,1H), 6.11 (d, J=2.3 Hz, 1H), 3.81 (d, J=15.3 Hz, 1H), 3.77 (d, J=15.3Hz, 1H), 2.83 (dd, J=12.5, 3.1 Hz, 1H), 2.76 (d, J=15.2 Hz, 1H), 2.67(d, J=15.2 Hz, 1H), 2.42 (m, 1H), 2.29 (m, 1H), 1.77-1.89 (m, 2H), 1.67(m, 1H), 1.35 (m, 1H), 1.20 (s, 3H).

Example 89

Step 1:

Example 22 (165.9 mg, 0.412 mmol) was dissolved in CH₂Cl₂ (20 mL) andthe solution was cooled to 0° C. 2,6-lutidine (265 μL, 2.27 mmol) andTBDMSOTf (142 μL, 0.618 mmol) were added and the reaction was allowed towarm to room temperature. After stirring for 16 h, additional2,6-lutidine (300 μL, 2.58 mmol) and TBDMSOTf (300 μL, 1.31 mmol) wereadded to the reaction. The reaction was stirred for an additional 3 hand then quenched with isopropyl alcohol (1 mL). The reaction wasdiluted with EtOAc (100 mL) and the organic solution was washed withsaturated NaHCO₃, brine, 1N HCl, saturated NaHCO₃, and brine (25 mL ofeach). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification by flash chromatography (15% TBME/hexanes)gave 207.1 mg (97%) of compound M. R_(f)=0.38 (15% EtOAc/hexanes). ¹HNMR (CDCl₃, 500 MHz) δ 7.37-7.39 (m, 2H), 7.26-7.30 (m, 3H), 7.18 (t,J=7.5 Hz, 1H), 7.10-7.14 (m, 4H), 5.98 (d, J=2.1 Hz, 1H), 4.24 (dd,J=10.5, 4.0 Hz, 1H), 2.96 (dd, J=13.0, 4.0 Hz, 1H), 2.72 (dd, J=13.0,10.5 Hz, 1H), 2.55 (d, J=15.3 Hz, 1H), 2.35 (m, 1H), 2.22 (bd, J=15.3Hz, 1H), 1.88 (m, 1H), 1.80 (m, 1H), 1.64-1.73 (m, 2H), 1.44 (dd,J=10.5, 3.0 Hz, 1H), 1.28 (m, 1H), 1.02 (s, 3H), 0.94 (s, 9H), 0.21 (s,3H), 0.19 (s, 3H).

Step 2:

CrO₃ (550 mg, 5.5 mmol) was placed in a 50 mL roundbottom flask equippedwith a stir bar, and 15 mL of dry CH₂Cl₂ was added. The suspension wascooled to −20° C. and 3,5-dimethylpyrrole (793 mg, 8.25 mmol) was added.The reaction was stirred for 15 min. at −20° C. and compound M (142 mg,0.275 mmol) was added by cannula in CH₂Cl₂ (6 mL). The reaction wasstirred for 1.5 h while the temperature was maintained between −20 and—15° C. The reaction was then diluted with 100 mL of 3:1 hexanes/Et₂Oand filtered through a plug of silica gel. The filtrate was concentratedand the residue was purified by flash chromatography with 15%EtOAc/hexanes and then with 2% TBME/toluene to afford 20.8 mg (14%) ofcompound N. R_(f)=0.29 (15% EtOAc/hexanes). LCMS=531; (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz) δ 7.44 (s, 1H), 7.39-7.41 (m, 2H), 7.29-7.32 (m, 2H),7.22 (s, 1H), 7.13-7.21 (m, 5H), 4.33 (dd, J=10.5, 4.0 Hz, 1H), 3.04(dd, J=13.0, 4.0 Hz, 1H), 2.70-2.79 (m, 3H), 2.32 (m, 1H), 2.01-2.07 (m,1H), 1.85 (d, J=16.1 Hz, 1H), 1.75 (m, 1H), 1.11 (s, 3H), 0.93 (s, 9H),0.24 (s, 3H), 0.20 (s, 3H).

Step 3:

Compound N (15.8 mg, 0.0298 mmol) was dissolved in THF (4.5 mL) and thesolution was cooled to −78° C. and MeLi (42 μL of a 1.4 M solution inEt₂O (0.0596 mmol)) was added dropwise by syringe. The reaction wasstirred for 15 min. at −78° C. and then quenched with isopropyl alcohol(100 μL). The cold solution was poured into saturated NH₄Cl (10 mL) andthe mixture was extracted with EtOAc (50 mL). The organic layer waswashed with H₂O and brine (15 mL each), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude residue (17.0 mg) was dissolved intoluene (2 mL) and p-toluenesulphonic acid monohydrate (5 mg, 0.0263mmol) was added. The reaction was stirred at room temperature for 15min. and then diluted with EtOAc (40 mL). The organic solution waswashed with saturated NaHCO₃ and brine (15 mL of each). The organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography (15% EtOAc/hexanes) toafford 5.7 mg (36%) of compound O. R_(f)=0.30 (15% EtOAc/hexanes).LCMS=529; (M+1)⁺. ¹H NMR (CDCl₃, 500 MEz) δ 7.40-7.43 (m, 3H), 7.25-7.28(m, 21), 7.12-7.18 (m, 51), 6.10 (s, 1H), 5.88 (d, J=5.5 Hz, 1H), 4.40(dd, J=10.3, 4.1 Hz, 1H), 2.95 (dd, J=13.0, 4.1 Hz, 1H), 2.70-2.75 (m,2H), 2.61 (m, 1H), 2.25 (dt, J=19.0, 5.0 Hz, 1H), 1.96 (d, J=15.4 Hz,1H), 1.76 (s, 3H), 1.73 (dd, J=12.5, 4.3 Hz, 1H), 1.04 (s, 3H), 0.94 (s,9H), 0.20 (s, 6H).

Step 4:

Compound O (5.7 mg, 0.0108 mmol) was dissolved in THF (3 mL) and TBAF(150 μL of a 1 M solution in TBF, 0.15 mmol) was added. The reaction wasstirred at room temperature for 3 h and then poured into saturated NH₄Cl(10 mL). The mixture was extracted with EtOAc (50 mL) and the organiclayer was washed with H₂O and brine (15 mL each), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bypreparatory thin layer chromatography (30% EtOAc/hexanes) to afford 3.5mg (78%) of Example 89. R_(f)=0.39 (40% EtOAc/hexanes). LCMS=415;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.46-7.48 (m, 2H), 7.43 (s, 1H), 7.41(t, J=7.5 Hz, 2H), 7.23-7.27 (m, 3H), 7.15-7.18 (m, 2H), 6.22 (s, 1H),5.92 (d, J=5.5 Hz, 1H), 4.31 (m, 1H), 2.97 (d, J=15.4 Hz, 1H), 2.86 (dd,J=13.0, 9.0 Hz, 1H), 2.70 (dd, J=13.0, 5.0 Hz, 1H), 2.63 (m, 1H), 2.48(d, J=15.1 Hz, 1H), 2.31 (dt, J=18.7, 5.0 Hz, 1H), 1.89 (dd, J=12.3, 4.3Hz, 1H), 1.83 (s, 3H), 1.14 (s, 3H).

Example 90

Step 1:

Ketone A (18.6 mg, 0.063 mmol) was dissolved in THF and cooled to ° C.BnMgCl (314 μL of a 1 M solution in TBF, 0.314 mmol) was added and thereaction was stirred at 0° C. for 1 hour. Saturated NH₄Cl (1 mL) wasadded to quench the reaction and the mixture was extracted with EtOAc(40 mL). The organic layer was washed with H₂O and brine (15 mL each),dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by flash chromatography (5 to 20% EtOAc/hexanes) to afford 14.0mg (57%) of Example 90. R_(f)=0.21 (25% EtOAc/hexanes). LCMS=389;(14+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.45-7.48 (m, 2H), 7.38 (s, 3H),7.15-7.30 (m, 7H), 6.26 (s, 1H), 3.52 (d, J=17.1 Hz, 1H), 2.98 (d,J=14.0 Hz, 1H), 2.86 (d, J=14.0 Hz, 1H), 2.68 (d, J=17.1 Hz, 1H), 2.61(m, 1H), 2.20 (dd, J=9.0, 4.4 Hz, 1H), 1.61-1.75 (m, 3H), 1.46 (m, 1H),1.37 (s, 3H).

Example 91

Step 1:

A solution of t-BuLi (150 μL of a 1.7 M solution in pentanes, 0.258mmol) in Et₂O (5 mL) was cooled to −78° C. and aldehyde B (16.0 mg,0.0516 mmol) was added as a solution in TEF (2 mL). The reaction wasallowed to warm slowly to −20° C. and then cooled back to −78° C. Thereaction was quenched by the addition of isopropyl alcohol (1 mL) andthen poured into saturated NH₄Cl (10 mL). The mixture was extracted withEtOAc (40 mL), and the organic layer was washed with H₂O and brine (15mL each), dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography (5 to 20% EtOAc/hexanes) toafford 8.0 mg (42%) of 91. R_(f)=0.24 (25% EtOAc/hexanes). LCMS=369;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.43-7.46 (m, 2H, 7.41 (s, 1H), 7.14(t, J=8.5 Hz, 1H), 6.11 (d, J=1.6 Hz, 1H), 3.49 (s, 1H), 2.83 (d, J=15.1Hz, 1H), 2.45 (d, J=15.1 Hz, 1H), 2.39 (m, 1H), 2.32 (br d, J=14.6 Hz,1H), 1.59-1.86 (m, 3H), 1.41 (m, 1H), 1.07 (s, 3H), 0.96 (s, 9H).

Example 92

Step 1:

2-phenyl-1,3-dithiane (408 mg, 2.08 mmol) was dissolved in THF (8 mL)and cooled to −78° C. n-BuLi (865 μL of a 1.6 M solution in hexanes,1.38 mmol) was added and the reaction was warmed to 0° C. The reactionwas stirred at 0° C. for 30 min. and then cooled back to −78° C. Asolution of aldehyde B (53.7 mg, 0.173 mmol) was added in THF (2 mL) bycannula. The reaction was stirred at −78° C. for 10 min. and then warmedto 0° C. and stirred at that temperature for 1 hour. The reaction wasquenched with isopropyl alcohol (1 mL) and then poured into saturatedNH₄Cl (20 mL). The mixture was extracted with EtOAc (50 mL), and theorganic layer layer was washed with H₂O and brine (20 mL each), driedover Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by flash chromatography (5 to 15% EtOAc/hexanes) to afford 54.0mg (62%) of P. R_(f)=0.23 (25% EtOAc/hexanes). LCMS=507; (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz) δ 8.04 (d, J=7.6 Hz, 2H), 7.41-7.45 (m, 4H), 7.38 (s,1H), 7.32 (t, J=7.3 Hz, 1H), 7.13 (m, 2H), 6.04 (d, J=2.1 Hz, 1H), 4.12(m, 1H), 2.64-2.75 (m, 5H), 2.17-2.30 (m, 3H), 1.92-1.96 (m, 2H), 1.58(m, 1H), 1.37 (qd, J=13.5, 2.0 Hz, 1H), 1.18 (m, 1H), 1.00 (s, 3H), 0.90(m, 1H).

Step 2:

To dithiane P (10.3 mg, 0.020 mmol) was added CH₃CN (900 μL), toluene(200 μL), and H₂O (100 μL). The biphasic solution was stirredvigorously, and [bis(trifluoracetoxy)iodo]benzene (17.5 mg, 0.041 mmol)was added. After 15 min., an additional portion of[bis(trifluoracetoxy)iodo]benzene (25 mg, 0.058 mmol) was added. Thereaction was stirred for an additional 10 min. and then quenched withsaturated NaHCO₃ (5 mL). The mixture was extracted with EtOAc (40 mL),and the organic layer was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bypreparatory thin layer chromatography to yield 4.4 mg (52%) of 92.R_(f)=0.33 (25% EtOAc/hexanes, 2 elutions). LCMS=417; (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz) δ 7.90 (d, J=7.1 Hz, 2H), 7.62 (t, J=7.4 Hz, 1H),7.49-7.63 (m, 3H), 7.42-7.45 (m, 2H), 7.13-7.17 (m, 2H), 6.08 (d, J=2Hz, 1H), 5.44 (d, J=6.2 Hz, 1H), 3.79 (d, J=6.2 Hz, 1H), 3.30 (d, J=14.6Hz, 1H), 2.85 (d, J=14.7 Hz, 1H), 2.36 (m, 1H), 2.22 (m, 1H), 1.90 (dd,J=12.5, 2.0 Hz, 1H), 1.76 (m, 1H), 1.70 (dd, J=12.5, 2.0 Hz, 1H), 1.29(s, 3H), 1.10-1.18 (m, 2H).

Example 42 (50 mg, 0.13 mmol) was dissolved in CH₂Cl₂ (8 mL) and NMO(22.8 mg, 0.195 mmol) was added. The reaction was stirred at 0° C. for 5min. and TPAP (4.5 mg, 0.013 mmol) was added. Stirring was continued at0° C. for an additional 1 h. The reaction was diluted with hexanes (2mL) and filtered through a plug of silica gel with 10% EtOAc/hexanes toafford 40 mg (80%) of Example 93 as a yellow oil. R_(f)=0.35 (25%EtOAc/hexanes). LCMS=393; (M+1)⁺.

Example 93 (20 mg, 0.051 mmol) was dissolved in diethyl ether (5 mL) andthe solution was cooled to −78° C. Phenyl lithium (300 μL of a 1.8 Msolution in Et₂O (0.53 mmol)) was added dropwise by syringe. Thereaction was stirred for 1 h at −78° C. and then quenched with isopropylalcohol (500 μL). The cold solution was poured into saturated NH₄Cl (10mL) and the mixture was extracted with EtOAc (50 mL). The organic layerwas washed with H₂O and brine (15 mL each), dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by reverse-phaseHPLC (20% AcCN/H₂O) to afford 16 mg (67%) of Example 94 as a singlediastereomer. R_(f)=0.20 (30% EtOAc/hexanes). LCMS=471; (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz) δ 7.61-7.59 (m, 1H), 7.49-7.45 (m, 1H), 7.35-7.27 (m,1H), 7.32-7.11 (m, 9H), 7.03-7.02 (dd, J=3.5, 4.8 Hz, 1H), 6.13 (br s,1H), 2.76 (dd, J=3.4, 11.0 Hz, 1H), 2.58 (d, J=16 Hz, 1H), 2.45-2.39 (m,3H), 2.23 (d, J=16.0 Hz, 1H), 1.04 (s, 3H).

Example 93 (20 mg, 0.051 mmol) was dissolved in diethyl ether (5 mL) andthe solution was cooled to −78° C. Methyl lithium (760 μL of a 1.4 Msolution in Et₂O) was added dropwise by syringe. The reaction wasstirred for 3 h at −78° C. and then quenched with isopropyl alcohol (1mL). The cold solution was poured into saturated NH₄Cl (10 mL) and themixture was extracted with EtOAc (50 mL). The organic layer was washedwith H₂O and brine (15 mL each), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash chromatography(30% EtOAc/hexanes) to afford 8.8 mg (42%) of Example 95. R_(f)=0.60(30% EtOAc/hexanes). LCMS=409; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ7.48-7.45 (m, 2H), 7.31-7.27 (m, 2H), 7.29-7.14 (m, 1H), 6.13 (br s,1H), 3.29 (d, J=16 Hz, 1H), 2.70 (d, J=16 Hz, 1H), 2.39-2.28 (m, 2H),2.08-2.05 (m, 2H), 1.71 (s, 3H), 1.66-1.57 (m, 4H), 1.28 (s, 3).

Example 95 (6.2 mg, 0.015 mmol) was dissolved in dichloromethane (7 mL)and the solution was cooled to 0° C. Boron trifluoride diethyl etherate(19 μL, 0.15 mmol) and triethylsilane (24 μL, 0.15 mmol) were addeddropwise by syringe. The reaction was stirred for 1 h at 0° C. and thenquenched with saturated NaHCO₃ (2 mL). The solution was poured into H₂O(10 mL) and the mixture was extracted with EtOAc (75 mL). The organiclayer was washed with H₂O and brine (15 mL each), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by flashchromatography (20% EtOAc/hexanes) to afford 3.5 mg (59%) of Example 96.R_(f)=0.60 (15% EtOAc/hexanes). LCMS=393; (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.47-7.46 (m, 3H), 7.24 (dd, J=4.9, 3.0 Hz, 1H), 7.17-7.14 (m,3H), 6.13 (br s, 1H), 3.41-3.39 (dq, J=7.3 Hz, 2.3 Hz, 1H), 3.11 (d,J=15.4 Hz, 1H), 2.75 (d, J=15.4 Hz, 1H), 2.32-2.23 (m, 2H), 1.89-1.84(m, 2H), 1.71 (dt, J=5.4, 2.8 Hz, 1H), 1.41-1.38 (m, 1H), (d, J=7.3 Hz,3H), 1.33-1.24 (m, 2H), 0.84 (s, 3H).

Example 35 and IPAP and NMO were processed as in Example 93 to providethe desired compound. R_(f)=0.40 (25% EtOAc/hexanes). LCMS=393; (M+1)⁺.¹H NMR (CDCl₃, 500 MHz) δ 7.99-7.97 (m, 2H), 7.61-7.59 (m, 1H), 7.52 (t,J=8.5 Hz, 1H), 7.47-7.43 (m, 4H), 7.19 (t, J=8.5 Hz, 1H), 6.19 (br s,1H), 3.73-3.70 (dd, J=9.6 Hz, 2.7 Hz, 1H), 2.73 (d, J=15.6 Hz, 1H),2.51-2.40 (m, 2H), 2.38-2.35 (m, 1H), 2.07-1.99 (m, 2H), 1.81-1.77 (m,1H), 1.27 (s, 3H).

Example 97 and MeLi were processed as in Example 95 to provide thedesired compound. R_(f)=0.30 (25% EtOAc/hexanes). LCMS=403; (M+1)⁺. ¹HNMR (CDCl₃, 500 MHz) δ 7.53-7.30 (m, 8H), 7.17-7.13 (m, 2H), 6.11 (br s,1H), 3.16-3.13 (d, J=16 Hz, 1H), 2.65-2.61 (d, J=16 Hz, 1H), 2.47-2.30(m, 2H), 1.70 (s, 3H), 1.63-1.52 (m, 2H), 1.29 (s, 3H).

The following compounds were synthesized following procedures analogousto those described for examples 93 and 95:

Com- LCMS pound Molecular structure (M + 1)⁺ 99

405 100

405 101

423 102

421 103

421 104

439

Example 105 and 106

Step 1: Addition of Grignard Reagents to Aldehyde F

Aldehyde F (16.7 mg, 0.0564 mmol) was dissolved in THF (3 mL) and cooledto 0° C. 3-butenyl magnesium chloride (1.1 mL of a 0.5 M solution inTHF, 0.564 mmol) was added dropwise by syringe. The reaction was stirredat 0° C. for 1 hour and then quenched with saturated NH₄Cl (10 mL). Themixture was extracted with EtOAc (40 mL) and the organic layer waswashed with H₂O and brine (10 mL each), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The two diastereomeric products were isolated byflash chromatography (5 to 20% EtOAc/hexanes) to afford 9.6 mg (48%) ofthe less polar diastereomer and 5.0 mg (25%) of the more polardiastereomer. Less Polar diastereomer: R_(f)=0.17 (25% EtOAc/hexanes).LCMS=353; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.44-7.47 (m, 2H), 7.40 (s,1H), 7.14 (t, J=8.5 Hz, 2H), 6.13 (s, 1H), 5.88 (m, 1H), 5.10 (dd, J=17,1.4 Hz, 1H), 5.02 (d, J=10.3 Hz, 1H), 3.77 (m, 1H), 2.85 (d, J=15.3 Hz,1H), 2.61 (m, 1H), 2.57 (d, J=15.3 Hz, 1H), 2.42 (m, 1H), 2.29 (m, 1H),2.20 (m, 1H), 2.05 (m, 1H), 1.81-1.91 (m, 2H), 1.72 (m, 1H), 1.60 (m,1H), 1.00 (s, 3H).

More Polar diastereomer: R_(f)=0.12 (25% EtOAc/hexanes). LCMS=353;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.45-7.48 (m, 2H), 7.39 (s, 1H), 7.14(t, J=9.0 Hz, 2H), 6.13 (s, 1H), 5.88 (m, 1H), 5.09 (dd, J=17, 1.4 Hz,1H), 5.01 (d, J=10.0 Hz, 1H), 3.71 (m, 1), 3.13 (d, J=15.3 Hz, 1H), 2.65(d, J=15.3 Hz, 1H), 2.60 (m, 1H), 2.45 (m, 1H), 2.29 (m, 1H), 2.19 (m,1H), 1.83-1.91 (m, 2H), 1.72 (m, 1H), 1.45-1.56 (m, 2H), 1.04 (s, 3H).

The following compounds were synthesized following procedures analogousto those described for examples 105 and 106:

Com- LCMS pound Molecular structure (M + 1)⁺ 107

389 108

389 109

423 110

423 111

425 112

425 113

403 114

403

Example 115 and 116

Step 1: Addition of Aryl Lithium Reagents to Aldehyde F

A solution of 1-Bromo-4-fluorobenzene (85 μL, 0.777 mmol) in Et₂O (8 mL)was cooled to −780C and tBuLi (914 μL of a 1.7 M solution in pentanes,1.55 mmol) was added dropwise by syringe. The reaction was stirred at−78° C. for 20 minutes and then aldehyde F (23.0 mg, 0.0777 mmol) in IBF(2 mL) was added by cannula. The reaction was stirred at −78° C. for 45minutes. 1 mL of isopropyl alcohol was added at −78° C. and then thereaction was poured into saturated NH₄Cl (10 mL). The mixture wasextracted with EtOAc (50 mL) and the organic layer was washed with waterand brine (15 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by flashchromatography (5 to 20% EtOAc/hexanes) yielded a mixture of 2diastereomers. Further purification by PTLC (20/60/20hexanes/CH₂Cl₂/Et₂O) afforded 13.8 mg (45%) of the less polardiastereomer and 9.0 mg (30%) of the more polar diastereomer.

Less Polar diastereomer (115): R_(f)=0.42 (20/60/20hexanes/CH₂Cl₂/Et₂O). LCMS=393; (M+1)⁺. ¹H NMR (CDCl₃, 500 Mz): δ7.36-7.43 (m, 4H), 7.19 (s, 1H), 7.08-7.14 (m, 4H), 6.11 (s, 1H), 4.66(d, J=8.5 Hz, 1H), 2.63 (m, 1H), 2.45 (m, 1H), 2.22-2.32 (m, 2H), 2.09(d, J=15.6 Hz, 1H), 1.95 (m, 1H), 1.71 (d, J=15.6 Hz, 1H), 1.00 (s, 3H).

More Polar diastereomer (116): R_(f)=0.20 (20/60/20 hexanes/CH₂Cl₂Et₂O).LCMS=393; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.45-7.48 (m, 2H), 7.41 (s,1H), 7.33-7.36 (m, 2H), 7.12-7.15 (m, 2H), 7.03-7.06 (m, 2H), 6.14 (s,1H), 4.64 (d, J=10.1 Hz, 1H), 3.25 (d, J=15.8 Hz, 1H), 2.78 (d, J=15.8Hz, 1H), 2.53 (m, 1H), 2.33 (m, 1H), 2.17 (m, Ii), 1.93 (br s, 1H), 1.46(m, 1H), 1.23 (m, 1H), 1.17 (s, 3H).

The following compounds were synthesized following procedures analogousto that described for Examples 115 and 116:

Com- LCMS pound Molecular structure (M + 1)⁺ 117

381 118

381 119

431 120

431 121

425 122

425 123

425 124

425 125

376 126

376 127

439 128

439 129

443 130

443 131

426 132

426 133

426 134

426 135

415 136

415

Example 137+138

Step 1: Addition of Lithium Reagents Generated by Deprotonation withBuLi to Aldehyde F

A solution of benzothiophene (403 μL, 3.45 mmol) in TBF (16 mL) wascooled to −78° C. and nBuLi (1.73 JnL of a 1.6 M solution in hexanes,2.76 mmol) was added dropwise by syringe. The reaction was warmed to 0°C. for 15 minutes and then cooled back to −78° C. Aldehyde F (68.1 mg,0.230 mmol) in THF (4 mL) was added by cannula and the reaction wasstirred at −78° C. for 45 minutes. 1 mL of isopropyl alcohol was addedat −78° C. and then the reaction was poured into saturated NH₄Cl (10mL). The mixture was extracted with EtOAc (50 mL) and the organic layerwas washed with water and brine (15 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo. Purification ofthe residue by flash chromatography (5 to 25% EtOAc/hexanes) gave theproduct as a mixture of diastereomers. The two diastereomers wereseparated by preparatory TLC in 40/40/20 CH₂Cl₂/hexanes/Et₂O followed bypreparatory TLC in 50/50/3 hexanes/CH₂Cl₂/MeOH. 22.6 mg of 137 (23%) and28.4 mg of 138 (29%) were isolated.

Characterization for 137: R_(f)=0.18 (25% EtOAc/hexanes). LCMS=431;(M+1)⁺. ¹H NMR (CDCl₃, 500 M) δ 7.87 (d, J=7.5 Hz, 1H), 7.79 (d, J=7.0Hz, 1H), 7.35-7.44 (m, 4H), 7.30 (s, 1H), 7.17 (s, 1H), 7.12 (m, 2H),6.14 (t, J=2 Hz, 1H), 5.07 (dd, J=8.5, 3 Hz, 1H), 2.66 (dd, J=19, 10.5Hz, 1H), 2.48 (m, 1H), 2.32-2.41(m, 3H), 2.07-2.10 (m, 2H), 1.98 (m,1H), 1.08 (s, 3H).

Characterization for 138: R_(f)=0.18 (25% EtOAc/hexanes). LCMS=431;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.84 (d, J=7.5 Hz, 1H), 7.73 (d, J=7.0Hz, 1H), 7.47 (m, 2H), 7.42 (s, 1H), 7.33 (m, 2H), 7.23 (s, 1H), 7.14(m, 2H), 6.16 (t, J=2.0 Hz, 1H) 5.02 (dd, J=10.0, 3.0 Hz, 1H), 3.25 (d,J=15.5 Hz, 1H), 2.81 (d, J=15.5 Hz, 1H), 2.58 (m, 1H), 2.34-2.44 (m,2H), 2.11 (d, J=3 Hz, 1H), 1.55 (m, 1H), 1.19 (s, 3H).

The following compounds were synthesized following procedures analogousto that described for examples 137 and 138:

Com- LCMS pound Molecular structure (M + 1)⁺ 139

432 140

432 141

543 142

543

Example 143

Step 1: Addition of Lithium Reagents Generated by Deprotonation withBuLi to Aldehyde B

A solution of thiophene (82 μL, 1.021 mmol) in THF (8 mL) was cooled to−78° C. and nBuLi (510 μL of a 1.6 M solution in hexanes, 0.816 mmol)was added dropwise by syringe. The reaction was warmed to 0° C. for 15minutes and then cooled back to −78° C. Aldehyde B (21.1 mg, 0.068 mmol)in THF (2 mL) was added by cannula and the reaction was stirred at −78°C. for 45 minutes. 1 mL of isopropyl alcohol was added at −78° C. andthen the reaction was poured into saturated NH₄Cl (10 mL). The mixturewas extracted with EtOAc (50 mL) and the organic layer was washed withwater and brine (15 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification of the residue byflash chromatography (5 to 15% EtOAc/hexanes) afforded 20.5 mg (76%) of143. R_(f)=0.18 (25% EtOAc/hexanes). LCMS=395; (M+1)⁺. ¹H NMR (CDCl₃,500 MHz) δ 7.44-7.46 (m, 21), 7.43 (s, 1H), 7.22 (dd, J=5.0, 1.0 Hz,1H), 7.14-7.17 (m, 2H), 6.99 (dd, J=5.0, 3.5 Hz, 1H), 6.95 (d, J=3.5 Hz,1H), 6.12 (d, J=2.2 Hz, 1H), 5.38 (s, 1H), 3.10 (d, J=15.1 Hz, 1H), 2.70(d, J=15.1 Hz, 1H), 2.42 (m, 1H), 2.31 (m, 1H), 2.2 (br s, 1H), 1.91(dd, J=12.3, 3.4 Hz, 1H), 1.88 (m, 1H), 1.70-1.79 (m, 2H), 1.33 (m, 1H),1.23 (s, 3H).

The following compounds were synthesized following procedures analogousto that described in Example 143:

Com- LCMS pound Molecular structure (M + 1)⁺ 144

445 145

413 146

429 147

396

The following compounds were synthesized following procedures analogousto those described for examples 93 and 95 and starting from example115/116:

Com- pound Molecular structure LCMS (M + 1)⁺ 148

391 149

407

Example 150

Step 1. Reduction of Ketone

Example 88 (10.0 mg, 0.025 mmol) was dissolved in THF (1 mL) and MeOH (1mL) was added. The solution was cooled to 0° C. and NaBH (15 mg, 0.125mmol) was added. The reaction was stirred at 0° C. for 2 hours and thenquenched with saturated NH₄Cl (1 mL). The mixture was extracted withEtOAc (25 mL) and the organic layer was washed with H₂O and brine (5 mLeach). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by PTLC to afford 7.9 mg(79%) of alcohol as a 3:1 mixture of diastereomers favoring 150 over 22.Further purification by chiral HPLC (OD column, 35% IPA/heptanes) gave4.7 mg (47%) of pure 150 (slower eluting isomer). R_(f)=0.23 (25%EtOAc/hexanes). LCMS=403; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.45-7.47(m, 2H), 7.40 (s, 1H), 7.36 (t, J=7.4 Hz, 2H), 7.28 (t, J=7.7 Hz, 3H),7.14-7.17 (m, 2H), 6.14 (s, 1H), 4.02 (m, 1H), 3.22 (d, J=15.5 Hz, 1H),3.03 (d, J=12.5 Hz, 1H), 2.71 (d, J=15.5 Hz, 1H), 2.60 (dd, J=13.1, 10.6Hz, 1H), 2.36 (m, 2H), 2.02 (m, 1H), 1.93 (m, 1H), 1.86 (dt, J=12.4, 3.6Hz, 1H), 1.39-1.55 (m, 2H), 1.14 (s, 3H).

Example 151 and 152

Step 1.

Example 22 (21.3 mg, 0.053 mmol) was dissolved in THE (3 mL) and PtO₂ (6mg) was added. The solution was placed under H₂ and stirred at roomtemperature. After 3 hours, the catalyst was filtered off and thefiltrate was concentrated. Purification by flash chromatography (5 to20% EtOAc/hexanes) afforded 7.7 mg (36%) of 151 as a white solid and 9.2mg (43%) of 152 as a white solid.

151 (Less Polar diastereomer): R_(f)=0.28 (25% EtOAc/hexanes). LCMS=405;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.44-7.46 (m, 2H), 7.38 (s, 1H), 7.27(t, J=7.4 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.13 (m, 4H), 4.22 (m, 1H),2.92 (d, J=16.0 Hz, 1H), 2.81 (dd, J=13.3, 8.9 Hz, 1H), 2.72 (dd,J=16.8, 6.2 Hz, 1H), 2.62 (dd, J=13.3, 4.5 Hz, 11), 2.54 (dd, J=16.9,6.1 Hz, 1H), 2.15 (d, J=16.0 Hz, 1H), 2.08 (br s, 1H), 1.86 (m, 1H),1.79 (m, 1H), 1.67-1.72 (m, 2H), 1.59 (m, 1H), 1.28-1.37 (m, 2H), 1.15(s, 3H).

152 (More Polar diastereomer): R_(f)=0.21 (25% EtOAc/hexanes). LCMS=405;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.46-7.48 (m, 2H), 7.42 (s, 1H), 7.35(t, J=7.6 Hz, 2H), 7.26 (t, J=7.9 Hz, 3H), 7.12-7.15 (m, 2H), 4.26 (m,1H), 2.90 (dd, J=13.3, 8.6 Hz, 1H), 2.74 (d, J=15.4 Hz, 1H), 2.72 (dd,J=13.3, 5.5 Hz, 1H), 2.53 (dd, J=16.3, 4.8 Hz, 1H), 2.38 (dd, J=16, 12Hz, 1H), 2.01 (d, J=15.1 Hz, 1H), 1.91 (m, 1H), 1.73 (m, 1H), 1.64 (m,1H), 1.57 (m, 1H), 1.51 (m, 1H), 1.34-1.43 (m, 2H), 1.29 (m, 1H), 0.95(s, 3H).

Example 153

Step 1. Cyclopropanation of the Alkene

A solution of Et₂Zn (410 μL of a 1 M solution in hexanes, 0.41 mmol) indichloroethane (1 mL) was cooled to 0° C. and CH₂I₂ (66 μL, 0.821 mmol)was added. The reaction was stirred for 5 minutes and the formation of awhite precipitate was observed. A solution of 43 (17.0 mg, 0.041 mmol)in dichloroethane (1 mL) was added by cannula. The reaction was warmedto room temperature and stirred for 1 hour. After this period of time,the reaction was quenched with 1 N HCl (1 mL). The mixture was extractedwith EtOAc (50 mL). The organic layer was washed with H₂O, aq. NaHSO₃,saturated NaHCO₃, and brine (15 mL each), dried over Na₂SO₄, filtered,and concentrated in vacuo. Purification of the residue by flashchromatography (5 to 20% EtOAc/hexanes) afforded 10.2 mg (58%) of 153.R_(f)=0.14 (25% EtOAc/hexanes). LCMS=429; (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.37-7.44 (m, 5H), 7.30 (t, J=7.4 Hz, 2H), 7.23 (t, J=7.4 Hz,1H), 7.12-7.16 (m, 2H), 6.05 (d, J=2.1 Hz, 1H), 3.59 (s, 1H), 2.79 (d,J=15.1 Hz, 1H), 2.19-2.31 (m, 31), 1.83 (dd, J=12.7, 3.0 Hz, 1H), 1.63(m, 1H), 1.11-1.34 (m, 1H), 1.04 (s, 3H) 1.00 (m, 1H), 0.89 (m, 1H),0.83 (m, 1H), 0.78 (m, 1H).

Example 154 was synthesized following procedures analogous to thatdescribed for Example 153:

Com- pound Molecular structure LCMS (M + 1)⁺ 154

381

Example 156

Step 1.

To a solution of aldehyde B (35.5 mg, 0.1145 mmol) in THF (200 μL) wasadded tBuOH (200 μL), 2-methyl-2-butene (200 μL), and a solution ofNaClO₂ (23 mg, 0.252 mmol) and NaH₂PO₄ (35 mg, 0.252 mmol) in H₂O (250μL). The reaction was stirred at room temperature for 2 hours and thenpartitioned between EtOAc and H₂O (25 mL of each). The aqueous layer wasacidified with 1N HCl and extracted with EtOAc (3×25 mL). All of theorganic extracts were combined and washed with brine (25 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by flash chromatography (40/60/1EtOAc/hexanes/HOAc) to afford 33.3 mg (89%) of acid 155. R_(f)=0.22(40/60/1 EtOAc/hexanes/HOAc). LCMS=327; (M+1)⁺.

Step 2. Coupling of Carboxylic Acid to Amine

To a solution of 155 (10.5 mg, 0.0322 mmol) in CH₃CN (0.5 mL) was addedDIPEA (23 μL, 0.129 mmol) and HATU (15 mg, 0.0387 mmol). The reactionwas stirred at room temperature for 5 minutes and then benzylamine (6μL, 0.0483 mmol) was added. After 30 minutes, the reaction was dilutedwith EtOAc (40 mL) and washed with saturated NaHCO₃, brine, 1 N HCl,saturated NaHCO₃, and brine (10 mL each). The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification by flashchromatography (20 to 60% EtOAc/hexanes) afforded 9.4 mg (70%) of 156.R_(f)=0.22 (40% EtOAc/hexanes). LCMS=416; (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.41-7.44 (m, 2H), 7.29-7.38 (m, 6H), 7.12-7.16 (m, 2H), 6.11 (d,J=1.8 Hz, 1H), 5.87 (t, J=5.4 Hz, 1H), 4.47 (m, 2H), 2.81 (d, J=15.3 Hz,1H), 2.68 (d, J=15.3 Hz, 1H), 2.43 (m, 1H), 2.29 (m, 1H), 2.25 (dd,J=12.7, 3.3 Hz, 1H), 1.97 (qd, J=13, 3.4 Hz, 1H) 1.89 (m, 1H), 1.79 (m,1H), 1.37 (m, 1H), 1.19 (s, 3H).

Example 157 was synthesized following procedures analogous to thatdescribed for Example 156:

Com- LCMS pound Molecular structure (M + 1)⁺ 157

402

Example 159

Step 1.

To a 0° C. solution of 87 (35.4 mg, 0.113 mmol) in CH₂Cl₂ was addedpyridine (270 μL, 2.72 mmol) and MsCl (105 μL, 1.36 mmol). The reactionwas stirred at 0° C. for 1 hour and then diluted with EtOAc (50 mL). Theorganic solution was washed with saturated NaHCO₃, H₂O, 1 N HCl, andbrine (10 mL each). The organic layer was dried over Na₂SO₄, filtered,and concentrated in vacuo. The crude residue was dissolved in DMPU (4mL) and NaN₃ (37 mg, 0.565 mmol) was added. The reaction was stirred atroom temperature for 3 days and then heated to 50° C. for 6 hours. Thereaction was cooled to room temperature, diluted with EtOAc (50 μL), andwashed with H₂O and brine (10 mL each). The organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification by flashchromatography (20% EtOAc/hexanes) afforded 32.2 mg (84%) of 158.R_(f)=0.38 (25% EtOAc/hexanes). LCMS=338; (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.43-7.46 (m, 21), 7.41 (s, 1H), 7.13-7.17 (m, 2H), 6.14 (d,J=1.9 Hz, 1H), 3.61 (dd, J=12.1, 3.7 Hz, 1H), 3.11 (dd, J=12.0, 9.7 Hz,1H), 2.91 (d, J=15.4 Hz, 1H), 2.63 (d, J=15.4 Hz, 1H), 2.29-2.40 (m,2H), 1.97 (m, 1H), 1.87 (m, 1H), 1.71 (m, 1H), 1.31-1.43 (m, 2H), 0.96(s, 3H).

Step 2.

To a solution of 158 (3.8 mg, 0.0113 mmol) in THF (300 μL) was addedtriphenylphosphine (10 mg, 0.0381 mmol) and water (20 μL). The reactionwas stirred at room temperature overnight, and then DIPEA was added (50μL). The reaction was diluted with CH₂Cl₂ (30 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was dissolved in CH₂Cl₂(1 mL) and DIPEA (100 μL, 0.574 mmol) and benzoyl chloride (20 μL, 0.172mmol) were added. The reaction was stirred at room temperature for 10minutes, diluted with EtOAc (25 mL) and washed with saturated NaHCO₃,brine, 1 N HCl, and brine (5 mL each). The organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification by flashchromatography (60% EtOAc/hexanes) afforded 4.1 mg (88%) of 159.R_(f)=0.35 (60% EtOAc/hexanes). LCMS=416; (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.78 (d, J=7.4 Hz, 2H), 7.43-7.52 (m, 6H), 7.15 (t, J=8.5 Hz,2H), 6.20 (s, 1H), 6.13 (d, J=1.6 Hz, 1H), 3.75 (m, 1H), 3.32 (m, 1H),3.07 (d, J=15.3 Hz, 1H), 2.78 (d, J=15.3 Hz, 1H) 2.40 (m, 1H), 2.32 (m,1H), 1.88 (m, 2H), 1.76 (m, 1H), 1.32-1.50 (m, 2H), 1.05 (s, 3H).

The following compounds were synthesized following procedures analogousto that described for Example 159:

Compound Molecular structure LCMS (M + 1)⁺ 160

380 161

430 162

394 163

382

Example 164

Step 1.

To a solution of 145 (7.4 mg, 0.018 mmol) in THF (1 mL) was added LAH(144 μL of a 1 M solution in Et₂O, 0.144 mmol). The reaction was stirredat room temperature for 24 hours and then added slowly to a mixture ofEt₂O/1N HCl (10/1, 20 mL). The mixture was washed with H₂O and brine (5mL each), dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification of the residue by flash chromatography (5 to 20%EtOAc/hexanes) afforded 4.5 mg (61%) of 164. R_(f)=0.17 (25%EtOAc/hexanes). LCMS=415; (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.45-7.47(m, 2H), 7.43 (s, 1H), 7.40 (d, J=7.4 Hz, 2H), 7.33 (t, J=7.7 Hz, 2H),7.25 (t, J=7.3 Hz, 1H), 7.15 (t, J=8.5 Hz, 2H), 6.62 (d, J=15.9 Hz, 1H),6.31 (dd, J=16.0, 5.4 Hz, 1H), 6.12 (d, J=1.8 Hz, 1H), 4.73 (d, J=5.0Hz, 1H), 3.09 (d, J=15.1 Hz, 1H), 2.62 (d, J=15.1 Hz, 1H), 2.42 (m, 1H),2.32 (m, 1H), 1.91 (m, 1H), 1.79 (m, 1H), 1.67-1.72 (m, 2H), 1.38 (m,1H), 1.22 (s, 3H).

Example 165

Step 1.

To a solution of 145 (12.9 mg, 0.031 mmol) in hexanes/TBF (3/1; 1.6 mL)was added Pd on CaCO₃ poisoned with lead (4 mg) and quinoline (15 μL).The mixture was stirred at room temperature for 15 minutes and thenplaced under H₂. The reaction was stirred at room temperature for 2hours and then the catalyst was removed by filtration. The filtrate wasdiluted with EtOAc (35 mL), washed with 1 N HCl and brine (10 mL each),dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification ofthe residue by flash chromatography (5 to 20% EtOAc/hexanes) afforded7.3 mg (56%) of 165. R_(f)=0.17 (25% EtOAc/hexanes). LCMS=415; (M+1)⁺.¹H NMR (CDCl₃, 500 MHz) δ 7.38-7.44 (m, 4H), 7.32-7.35 (m, 4H), 7.14 (t,J=8.6 Hz, 2H), 6.56 (d, J=11.7 Hz, 1H), 6.08 (d, J=1.8 Hz, 1H), 5.90(dd, J=11.7, 9.0 Hz, 1H), 4.91 (d, J=8.9 Hz, 1H), 2.76 (d, J=15.2 Hz,1H), 2.29-2.42 (m, 3H), 1.88-1.96 (m, 2H), 1.77 (qd, J=9.6, 3.3 Hz, 1H),1.62 (dd, J=12.5, 2.4 Hz, 1H), 1.41 (m, 1H), 1.10 (s, 3H).

Example 166+167

Step 1: Addition of Lithium Phenyl Sulfone Reagent to Aldehyde F

A solution of methyl phenyl sulfone (285 mg, 1.83 mmol) in THF (16 mL)was cooled to 0° C. and nBuLi (950 μL of a 1.6 M solution in hexanes,1.52 mmol) was added dropwise by syringe. The reaction was stirred at 0°C. for 1 hour and then it was further cooled to −78° C. Aldehyde F (45.1mg, 0.152 mmol) in THF (4 mL) was added by cannula. The reaction wasstirred at −78° C. for 45 minutes. 1 mL of isopropyl alcohol was addedat −78° C. and then the reaction was poured into saturated NH₄Cl (25mL). The mixture was extracted with EtOAc (50 mL) and the organic layerwas washed with water and brine (15 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo. Purification byflash chromatography (10 to 50% EtOAc/hexanes) yielded a mixture of 2diastereomers. Further purification by PTLC (20/40/40hexanes/CH₂Cl₂/Et₂O) afforded 24.4 mg (35%) of the less polardiastereomer and 11.3 mg (16%) of the more polar diastereomer.

Less Polar diastereomer: R_(f)=0.32 (50% EtOAc/hexanes). LCMS=453;(M+1)⁺. ¹H NMR (CDCl₃, 600 MHz): δ 7.98 (d, J=7.8 Hz, 2H), 7.70 (t,J=7.5 Hz, 1H), 7.61 (t, J=7.8 Hz, 2H), 7.42 (m, 2H), 7.36 (s, 1H), 6.08(s, 1H), 4.32 (m, 1H), 3.48 (s, 1H), 3.32 (m, 2H), 2.67 (d, J=15 Hz,1H), 2.57 (m, 1H), 2.51 (d, J=15 Hz, 1H), 2.15 (s, 1H), 1.99 (m, 1H),1.91 (m, 1H), 1.83 (m, 1H), 0.89 (s, 3H).

More Polar diastereomer: R_(f)=0.32 (50% EtOAc/hexanes). LCMS=453;(M+1)⁺. ¹H NMR (CDCl₃, 600 MHz): δ 7.95 (d, J=8.4 Hz, 2H), 7.68 (m, 1H),7.61 (t, J=9 Hz, 2H), 7.45 (m, 2H), 7.38 (s, 1H), 7.13 (t, J=9 Hz, 2H),6.11 (s, 1H), 4.26 (m, 1H), 3.27 (s, 2H), 3.15 (d, J=19.2 Hz, 2H), 2.63(d, J=19.2 Hz, 1H), 2.57 (m, 1H), 2.42 (m, 1H), 2.15 (s, 1H), 1.98 (m,1H), 1.71 (m, 2H), 1.42 (m, 1H), 1.03 (s, 3H).

Starting from the appropriate aldehyde, the following compounds weresynthesized following procedures analogous to those described forexamples 166 and 167:

Compound Molecular structure LCMS (M + 1)⁺ 168

467 169

467

Epoxide Q/R

Step 1:

Trimethyl sulfoxonium iodide (240 mg, 1.09 mmol) was added as a solid toa suspension of sodium hydride (36.5 mg, 0.91 mmol of a 60% dispersionin mineral oil) in DMSO (2 mL). The reaction was stirred at roomtemperature for 10 minutes. Aldehyde F (54.0 mg, 0.18 mmol) in THF (4mL) was added by cannula. The reaction was stirred at room temperaturefor 2 hours. 1 mL of water was added and then the reaction was pouredinto saturated NaHCO₃ (25 mL). The mixture was extracted with EtOAc (50mL) and the organic layer was washed with water and brine (15 mL each).The organic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by flash chromatography (5 to 40% EtOAc/hexanes)yielded 8.8 mg (16%) of the less polar diastereomer and 11.2 mg (20%) ofthe more polar diastereomer.

Less Polar diastereomer: R_(f)=0.56 (50% EtOAc/hexanes). LCMS=311;(M+1)⁺. ¹H NMR (CDCl₃, 600 MHz): δ 7.15 (m, 2H), 6.91 (s, 1H), 6.80 (t,J=8.7 Hz, 2H), 5.85 (s, 1H), 2.56 (m, 1H), 2.44 (d, J=15.6 Hz, 1H), 2.32(m, 1H), 2.24 (m, 1H), 2.18 (d, J=15.6 Hz, 1H), 2.12 (m, 1H), 2.02 (m,1H), 1.45 (m, 2H), 1.31 (m, 1H), 0.63 (s, 3H).

More Polar diastereomer: R_(f)=0.52 (50% EtOAc/hexanes). LCMS=311;(M+1)⁺. ¹H NMR (CDCl₃, 600 MHz): δ 7.12 (m, 2H), 6.94 (s, 1H), 6.84 (t,J=8.7 Hz, 2H), 5.82 (s, 1H), 2.50 (m, 1H), 2.47 (s, 1H), 2.79 (m, 1H),2.17 (m, 2H), 2.07 (m, 2H), 1.44 (m, 2H), 1.19 (m, 1H), 0.67 (s, 3H).

Starting from the appropriate aldehyde, the following compounds weresynthesized following procedures analogous to those described for Q/R:

Compound Molecular structure LCMS (M + 1)⁺ S

326 T

326

Example 170 and 171

Step 1: Addition of Lithium Phenyl Sulfone Reagent to Epoxide R

A solution of methyl phenyl sulfone (305 mg, 1.92 mmol) in TBF (12 mL)was cooled to 0° C. and nBuLi (1 mL of a 1.6 M solution in hexanes, 1.6mmol) was added dropwise by syringe. The reaction was stirred at 0° C.for 30 min. and then cooled to −78° C. Epoxide R (10 mg, 0.032 mmol) inTBF (2 mL) was added by cannula. The reaction was stirred at −78° C. for45 minutes. The reaction was warmed to room temperature and left at roomtemperature overnight. After stirring overnight at room temperature, 1mL of isopropyl alcohol was added, and the reaction was poured intosaturated NH₄Cl (10 mL). The mixture was extracted with EtOAc (25 mL)and the organic layer was washed with water and brine (10 mL each). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by flash chromatography (5 to 100% EtOAc/hexanes)yielded a mixture of desired product and minor impurities. Furtherpurification by PTLC (20/40/40 hexanes/CH₂Cl₂/Et₂O) afforded 4.9 mg(33%) of 170. R_(f)=0.17 (50% EtOAc/hexanes). LCMS=467; (M+1)⁺. ¹H NMR(CDCl₃, 600 MHz): δ 7.94 (d, J=7.8 Hz, 2H), 7.68 (t, J=7.5 Hz, 1H), 7.59(t, J=7.8 Hz, 2H), 7.45 (m, 2H), 7.37 (s, 1H), 7.13 (t, J=8.1 Hz, 2H),6.13 (s, 1H), 3.82 (t, J=7.8 Hz, 1H), 3.29 (m, 2H), 3.05 (d, J=15.6 Hz,1H), 2.61 (m, 1H), 2.45 (m, 1H), 2.12 (m, 1H), 1.83 (m, 4H), 1.64 (m,1H), 1.53 (m, 1H), 1.01 (s, 3H).

A solution of methyl phenyl sulfone (305 mg, 1.92 mmol) in TBF (12 mL)was cooled to 0° C. and nBuLi (1 mL of a 1.6 M solution in hexanes, 1.6mmol) was added dropwise by syringe. The reaction was stirred at 0° C.for 30 min and then cooled to −78° C. Epoxide Q (10 mg, 0.032 mmol) inTHF (2 mL) was added by cannula. The reaction was stirred at −78° C. for45 minutes. The reaction was warmed to room temperature and left at roomtemperature overnight. After stirring overnight at room temperature, 1mL of isopropyl alcohol was added and the reaction was poured intosaturated NH₄Cl (10 mL). The mixture was extracted with EtOAc (25 mL)and the organic layer was washed with water and brine (10 mL each). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by flash chromatography (5 to 100% EtOAc/hexanes)yielded a mixture of desired product and some minor impurities. Furtherpurification by PTLC (20/40/40 hexanes/CH₂Cl₂/Et₂O) afforded 3.2 mg ofexample 171 (21%). R_(f)=0.17 (50% EtOAc/hexanes). LCMS=467; (M+1)⁺. ¹HNMR (CDCl₃, 600 MHz): δ 7.96 (d, J=7.8 Hz, 2H), 7.69 (m, 1H), 7.61 (m,2H), 7.45 (m, 2H), 7.38 (s, 1H), 7.14 (t, J=7.8 Hz, 2H), 6.12 (s, 1H),3.87 (m, 1H), 3.34 (m, 2H), 2.75 (d, J=15.5 Hz, 1H), 2.60 (m, 1H), 2.53(d, J=15.5 Hz, 1H), 2.43 (m, 1H), 2.14 (m, 1H), 1.89 (m, 1H), 1.81 (m,3H), 0.96 (s, 3H).

Starting from the appropriate epoxide, the following compounds weresynthesized following procedures analogous to those described forexamples 170 and 171:

Com- pound Molecular structure LCMS (M + 1)⁺ 172

481 173

481

Example 174

Step 1: Addition of 1,2 Phenylenediamine to Aldehyde B.

1,2 Phenylenediamine (10.5 mg, 0.097 mmol) and aldehyde B (15.0 mg, 0.05mmol) were placed in a flask under nitrogen. Nitrobenzene (500 μL) wasadded, and the reaction was heated to 150° C. The reaction was stirredat 150° C. for 4 hours. After cooling to room temperature, the reactionwas loaded directyl onto silica gel and the column was eluted with 100%hexanes to remove the nitrobenzene, followed by 40 to 80% EtOAc/hexanesto afford a mixture of the desired product and some minor impurities.Further purification by PTLC (2/98 MeOH(CH₂Cl₂) gave 16.0 mg (84%) ofexample 174: R_(f)=0.19 (40% EtOAc/hexanes). LCMS=399; (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz): δ 7.55 (s, 1H), 7.39 (m, 2H), 7.26 (s, 1H), 7.20 (m,2H), 7.11 (t, J=8.5 Hz, 3H), 6.14 (s, 1H), 3.19 (m, 1H), 2.88 (d, J=15.5Hz, 1H), 2.63 (d, J=15.5 Hz, 1H), 2.40 (m, 2H), 2.21 (m, 2H), 1.94 (m,2H), 1.44 (m, 1H), 1.21 (s, 3H).

Starting from the appropriate aldehyde, the following compounds weresynthesized following procedures analogous to those described forBenzimidazole 174:

Compound Molecular structure LCMS (M + 1)⁺ 175

385 176

399

Example 177 and 178

Step 1. Addition of DAST to Example 119.

In a plastic vial, a solution of Example 119 (38.2 mg, 0.089 mmol) inCH₂Cl₂ (500 μL) was cooled to 0° C. and diethylamino sulfur trifluoride(23.6 μL, 0.178 mmol) was added dropwise by syringe. The reaction wasstirred at 0° C. for 10 minutes and then was warmed to room temperature.The reaction was stirred at room temperature for 2 hours. The reactionwas poured into saturated NaHCO₃ (10 mL). The mixture was extracted withEtOAc (50 mL) and the organic layer was washed with brine (15 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by flash chromatography (5 to 20% EtOAc/hexanes)yielded a mixture of 2 diastereomers, which were separated using an ODchiral column (15% IPA/heptanes) to yield 4.6 mg (12%) of peak 1 and 6.9mg (18%) of peak 2.

Peak 1: R_(f)=0.39 (40% EtOAc/hexanes). LCMS=433; (M+1)⁺. ¹H NMR (CDCl₃,500 MHz): δ 8.00 (d, J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.48 (m,2H), 7.46 (s, 1H), 7.15 (t, J=8.4 Hz, 2H), 6.17 (s, 1H), 5.81 (dd,J=47.4 Hz, 10.8 Hz, 1H), 3.21 (dd, J=15.9 Hz, 3.9 Hz, 1H), 2.88 (d,J=16.2 Hz, 1H), 2.80 (m, 1H), 2.59 (m, 1H), 2.40 (m, 1H), 1.59 (m, 1H),1.48 (m, 1H), 1.26 (s, 3H).

Peak 2: R_(f)=0.44 (40% EtOAc/hexanes). LCMS=433; (M+1)⁺. ¹H NMR (CDCl₃,500 MHz): δ 7.92 (d, J=1.8 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.49 (d,J=1.8 Hz, 1H), 7.41 (m, 4H), 7.14 (t, J=9 Hz, 2H), 6.14 (t, J=1.8 Hz,1H), 5.91 (dd, J=46.8 Hz, 6.6 Hz, 1H), 2.69 (m, 2H), 2.47 (m, 1H), 2.88(dd, J=38.7 Hz, 15 Hz, 2H), 2.17 (m, 1H), 1.21 (d, J=6 Hz, 1H), 1.15 (s,3H).

Aldehyde W

Step 1:

Trimethyl sulfoxonium iodide (334 mg, 1.52 mmol) was added as a solid toa suspension of sodium hydride (54 mg, 1.35 mmol of a 60% dispersion inmineral oil) in DMSO (4 mL). The reaction was stirred at roomtemperature for 10 minutes. Ketone A (100 mg, 0.338 mmol) in THF (0.5mL) was added by cannula. The reaction was stirred at room temperatureovernight. 1 mL of water was added and then the reaction was poured intosaturated NaHCO₃ (25 mL). The mixture was extracted with EtOAc (50 mL)and the organic layer was washed with water and brine (15 mL each). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by flash chromatography (5 to 40% EtOAc/hexanes)afforded 101.6 mg (97%) of U. R_(f)=0.56 (40% EtOAc/hexanes). LCMS=311;(M+1)⁺.

Step 2:

Trifluoroacetic acid (1.5 mL) was added to epoxide U (101.6 mg, 0.322mmol). This reaction was stirred at room temperature for 20 minutes. Thereaction was then poured into ice/H₂O and neutralized with 10% K₂CO₃.The mixture was extracted with EtOAc (20 mL) and the organic layer waswashed with water and brine (15 mL each). The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification by flashchromatography (5 to 40% EtOAc/hexanes) afforded 59.1 mg (58%) of V.R_(f)=0.42 (50% EtOAc/hexanes). LCMS=311; (M+1)⁺. ¹H NMR (CDCl₃, 600MHz): δ 7.29 (s, 1H), 7.64 (s, 1H), 7.51 (m, 2H), 7.16 (s, 1H), 7.12 (t,J=8.4 Hz, 2H), 3.69 (d, J=10.8 Hz, 1H), 3.45 (d, J=10.8 Hz, 1H), 2.82(m, 2H), 1.96 (m, 1H), 1.75 (m, 2H), 1.52 (m, 1H), 1.24 (m, 3H).

Step 3:

A solution of oxalyl chloride (75.4 μL, 0.86 mmol) in CH₂Cl₂ (4 mL) wascooled to −78° C. DMSO (122.7 μL, 1.73 mmols) was added. This reactionwas stirred at room temperature for 10 minutes. Alcohol V (53.6 mg,0.173 mmol) was dissolved CH₂Cl₂ (1 mL) and added to the reaction viacannula. This was stirred at −78° C. for 20 minutes. (482.0 μL, 3.46mmol) of triethyl amine was added at −78° C. and then the reaction waswarmed to room temperature. The mixture was extracted with EtOAc (20 mL)and the organic layer was washed with water, 1N HCl, NaHCO₃, and brine(15 mL each). The organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by flash chromatography (5 to 50%EtOAc/hexanes) afforded 39.8 mg (75%) of W. R_(f)=0.69 (50%EtOAc/hexanes). LCMS=309; (M+1)⁺. ¹H NMR (CDCl₃, 600 MHz): δ 9.55 (s,1H), 8.11 (s, 1H), 7.66 (m, 2H), 7.53 (s, 1H), 7.44 (s, 1H), 7.23 (t,J=8.4 Hz, 2H), 2.97 (m, 2H), 2.19 (m, 1H), 1.91 (m, 2H), 1.74 (m, 1H),1.54 (m, 3H).

The following compound was synthesized following procedures analogous tothose described for Aldehyde W starting from ketone A:

Compound Molecular structure LCMS (M + 1)⁺ X

309

Example 179 and 180

Step 1: Addition of Grignard Reagent to Aldehyde W

Aldehyde W (38.2 mg, 0.121 mmol) was dissolved in THF (6 mL) and cooledto 0° C. 4-fluorobenzyl magnesium bromide (310 μL of a 2.0 M solution indiethyl ether, 0.620 mmol) was added dropwise by syringe. The reactionwas stirred at 0° C. for 1 hour and then quenched with saturated NH₄Cl(10 mL). The mixture was extracted with EtOAc (40 mL) and the organiclayer was washed with H₂O and brine (10 mL each), dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by flashchromatography (5 to 80% EtOAc/hexanes) yielded a mixture of 2diastereomers, which were separated on an AD chiral column (30%IPA/heptanes) to afford 24.4 mg (49%) of peak 1 and 17.2 mg (34%) ofpeak 2.

Peak 1: R_(f)=0.11 (25% EtOAc/hexanes). LCMS=405; (M+1)⁺. ¹H NMR (CDCl₃,500 MHz): δ 8.03 (s, 1H), 7.83 (s, 1H), 7.56 (m, 2H), 7.15 (t, J=8.5 Hz,2H), 7.09 (m, 2H), 7.16 (s, 1H), 6.86 (t, J=8.8 Hz, 2H), 4.76 (s, 1H),2.72 (m, 2H), 2.43 (s, 1H), 1.97 (s, 1H), 1.74 (m, 2H), 1.46 (m, 1H),1.35 (s, 3H).

Peak 2: R_(f)=0.11 (25% EtOAc/hexanes). LCMS=405; (M+1)⁺. ¹H NMR (CDCl₃,500 MHz): δ 7.95 (s, 1H), 7.69 (s, 1H), 7.51 (m, 2H), 7.16 (s, 1H), 7.17(m, 2H), 7.09 (m, 2H), 6.86 (t, J=8.8 Hz, 2H), 4.95 (s, 1H), 2.78 (m,2H), 2.03 (m, 1H), 1.97 (s, 1H), 1.72 (s, 1H), 1.52 (m, 2H), 1.11 (s,3H).

The following compounds were synthesized following procedures analogousto those described for Examples 179 and 180 and starting from AldehydeX:

LCMS Compound Molecular structure (M + 1)⁺ 181

405 182

405

Example 183 and 184

Step 1: Addition of Aryl Lithium to Aldehyde W

A solution of 3-bromothianapthene (162.2 μL, 1.24 mmol) in Et₂O (16 mL)was cooled to −78° C. and t-BuLi (1.45 mL of a 1.7 M solution inpentanes, 2.48 mmol) was added dropwise by syringe. The reaction wasstirred at −78° C. for 20 minutes and then aldehyde W (38.2 mg, 0.124mmol) in THF (2 mL) was added by cannula. The reaction was stirred at−78° C. for 45 minutes. 1 mL of isopropyl alcohol was added at −78° C.and the reaction was poured into saturated NH₄Cl (10 mL). The mixturewas extracted with EtOAc (50 mL) and the organic layer was washed withwater and brine (15 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by flashchromatography (5 to 20% EtOAc/hexanes) yielded a mixture of 2diastereomers that were separated using an AD chiral column (25%IPA/heptanes) to yield 3.8 mg (6.9%) of Peak 1 and 6.7 mg (12%). Peak 2:

Peak 1: R_(f)=0.74 (40% EtOAc/hexanes). LCMS=443; (M+1)⁺. ¹H NMR (CDCl₃,500 MHz): δ 8.01 (s, 1H), 7.90 (s, 1H), 7.83 (m, 1H), 7.73 (m, 1H), 7.55(m, 1H), 7.16 (s, 1H), 7.19 (m, 2H), 5.23 (s, 1H), 2.72 (m, 2H), 2.09(s, 1H), 1.93 (s, 1H), 1.83 (m, 1H), 1.61 (m, 1H), 1.45 (s, 3H).

Peak 2: R_(f)=0.74 (40% EtOAc/hexanes). LCMS=443; (M+1)⁺. ¹H NMR (CDCl₃,500 MH): δ 7.90 (s, 1H), 7.78 (s, 1H), 7.69 (m, 1H), 7.64 (m, 1H), 7.51(m, 1H), 7.20 (s, 1H), 7.14 (m, 2H), 7.08 (s, 1H), 7.07 (t, J=9.0 Hz,2H), 5.47 (s, 1H), 2.73 (t, J=6.3 Hz, 1H), 2.17 (m, 1H), 1.93 (s, 1H),1.79 (m, 1H), 1.57 (m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 1.21 (s, 3H).

The following compounds were synthesized following procedures analogousto those described for Examples 183 and 184 and starting from aldehydeX:

LCMS Compound Molecular structure (M + 1)⁺ 185

443 186

443

Aldehyde Y

Step 1:

A suspension of (methoxymethyl)triphenylphosponium chloride (763 mg, 2.2mmol) in THF (8 mL) was cooled to 0° C. Potassium bis(trimethylsilylamide) (3.6 mL of a 0.5 M solution in toluene, 1.78 mmol) was addeddropwise by syringe and the reaction turned bright orange/red. Next, asolution of aldehyde F (132 mg, 0.44 mmol) in THF (4 mL) was added bycannula. The reaction was allowed to warm to room temperature. Afterstirring at room temperature for 2 hours, 4N HCl was added slowly andthe reaction was left stirring for another hour. The reaction was thendiluted with EtOAc (50 mL), quenched with NaHCO₃ (50 mL), and washedwith H₂O and brine (25 mL each). The organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byflash chromatography (5 to 35% EtOAc/hexanes) to afford 95.1 mg (69%) ofY. R_(f)=0.29 (25% EtOAc/hexanes). LCMS=311; (M+1)⁺. ¹H NMR (CDCl₃, 600MHz) δ 9.86 (t, J=2.1 Hz, 1H), 7.44-7.47 (m, 2H), 7.39 (s, 1H),7.13-7.16 (m, 1H), 6.17 (s, 1H), 2.68 (d, J=15.0 Hz, 1H), 2.60 (m, 2H),2.55 (d, J=15.0 Hz, 1H), 2.46 (m, 2H), 2.34 (m, 1H), 2.10 (m, 1H), 1.58(m, 2H), 0.93 (s, 3H).

Aldehyde Z

Aldehyde Z was synthesized from aldehyde B using the same procedure aswas used in the synthesis of aldehyde Y.

Example 187 and 188

Step 1: Addition of Grignard Reagent to Aldehyde Y

Aldehyde Y (53.0 mg, 0.17 mmol) was dissolved in THF (6 mL) and cooledto 0° C. 3-butenyl magnesium chloride (1.7 mL of a 0.5 M solution inTHF, 0.85 mmol) was added dropwise by syringe. The reaction was stirredat 0° C. for 1 hour and then 1 mL of isopropyl alcohol was added. Thereaction was then poured into saturated NH₄Cl (25 mL) and extracted withEtOAc (40 mL). The organic layer was washed with H₂O and brine (25 mLeach), dried over Na₂SO₄, filtered, and concentrated in vacuo. The twodiastereomeric products were isolated by flash chromatography (5 to 20%EtOAc/hexanes) to afford 17.3 mg (28%) of the less polar diastereomerand 19.9 mg (32%) of the more polar diastereomer. Less Polardiastereomer: R_(f)=0.15 (25% EtOAc/hexanes). LCMS=366; (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz): δ 7.44-7.47 (m, 2H), 7.33 (m, 2H), 7.30 (s, 1H),7.01(m, 1H), 5.73 (m, 1H), 4.95(m, 1H), 4.87 (dd, J=8.5, 1.8 Hz, 1H),4.86 (d, J=10.3 Hz, 2H), 3.63 (m, 1H), 2.62 (d, J=15.5 Hz, 1H), 2.47 (m,1H), 2.42 (d, J=7.5 Hz, 1H), 2.07 (m, 2H), 1.92 (m, 1H), 1.74 (m, 1H),1.38-1.56 (m, 6H), 0.80 (s, 3H).

More Polar diastereomer: R_(f)=0.14 (25% EtOAc/hexanes). LCMS=366;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.45 (m, 2H), 7.38 (m, 2H), 7.30 (s,1H), 7.12 (m, 2H), 6.12 (m, 1H), 5.85 (m, 2H), 5.07(m, 1H), 4.99 (dd,J=8.5, 1.8 Hz, 1H), 3.69 (m, 1H), 2.72 (d, J=15.5 Hz, 1H), 2.57 (m, 1H),2.51 (d, J=15.5 Hz, 1H), 2.51 (m, 1H), 2.41 (m, 1H), 2.19 (m, 2H), 2.07(m, 2H), 1.61-1.39 (m, 6H), 0.90 (s, 3H).

The following compounds were synthesized following procedures analogousto those described for examples 187 and 188:

Com- LCMS pound Molecular structure (M + 1)⁺ 189

403 190

403 191

407 192

407

The following compounds were synthesized following procedures analogousto those described for examples 187 and 188 and starting from aldehydeZ:

Com- LCMS pound Molecular structure (M + 1)⁺ 193

417 194

417 195

421 196

421 197

381 198

381

Example 199 and 200

Step 1: Addition of Aryl Lithium Reagents to Aldehyde Y

A solution of 1-Bromothianapthene (259 μL, 1.98 mmol) in Et₂O (8 mL) wascooled to −78° C. and t-BuLi (2.3 mL of a 1.7 M solution in pentanes,3.95 mmol) was added dropwise by syringe. The reaction was stirred at−78° C. for 20 minutes and then aldehyde Y (61.3 mg, 0.20 mmol) in ThF(2 mL) was added by cannula. The reaction was stirred at −78° C. for 45minutes. 1 mL of isopropyl alcohol was added at −78° C. and then thereaction was poured into saturated NH₄Cl (25 mL). The mixture wasextracted with EtOAc (50 mL) and the organic layer was washed with waterand brine (15 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by flashchromatography (5 to 20% EtOAc/hexanes) yielded a mixture of 2diastereomers. Further purification by PTLC (40/40/20hexanes/CH₂Cl₂/Et₂O) afforded 34.7 mg of the less polar diastereomercontaminated with minor impurities and 28.2 mg (32%) of the more polardiastereomer. Final purification of the less polar diastereomer using anAD Chiral Column (35% isopropyl alcohol/heptanes) afforded 22.3 mg (25%)of the less polar diastereomer.

Less Polar diastereomer: R_(f)=0.21 (25% EtOAc/hexanes). LCMS=445;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.86 (d, J=8 Hz, 1H), 7.80 (d, J=7.5Hz, 1H), 7.33 (m, 3H), 7.29 (s, 1H), 7.20 (s, 1H), 7.02 (m, 2H), 6.00(s, 1H), 5.09 (t, J=6.5 Hz, 1H), 2.64 (d, J=15 Hz, 1H), 2.48 (m, 1H),2.33 (d, J=15 Hz, 1H), 2.70(m, 1H), 2.13 (m, 1H), 1.97 (m, 1H), 1.87 (m,1H), 1.73 (m, 1H), 1.52 (m, 1H), 1.18 (m, 1H), 0.86 (s, 3H).

More Polar diastereomer: R_(f)=0.21 (25% EtOAc/hexanes). LCMS=445;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.88 (t, J=6 Hz, 2H), 7.34-7.45 (m,6H), 7.13 (t, J=6.25 Hz, 2H), 6.13 (s, 1H), 5.16 (d, J=6.5 Hz, 1H), 2.73(d, J=12.5 Hz, 1H), 2.59 (m, 1H), 2.54 (d, J=12.5 Hz, 1H), 2.46 (m, 1H),2.17 (m, 2H), 2.05 (m, 1H), 1.86 (m, 1H), 1.59 (m, 1H), 1.25 (m, 1H),0.90 (s, 3H).

The following compounds were synthesized following procedures us to thatdescribed for Examples 199 and 200:

Com- LCMS pound Molecular structure (M + 1)⁺ 201

408 202

408

The following compounds were synthesized starring from aldehyde Z andfollowing procedures analogous to that described for Examples 199 and200:

LCMS Compound Molecular structure (M + 1)⁺ 203

409 204

409 205

459 206

459

Example 207

Step 1

Example 61 (4.3 mg, 0.01 mmol) was dissolved in EtOAc (0.5 mL) and 10%Pd on activated carbon (1.0 mg) was added. The reaction was placed underH₂ and stirred at room temperature for 45 minutes. The catalyst wasremoved by filtration. The filtrate was concentrated, and the residuewas purified by preparatory thin layer chromatography (25%EtOAc/hexanes) to afford 2.8 mg (65%) of Example 207. R_(f)=0.15 (25%EtOAc/hexanes). LCMS=435; (M+1)⁺. ¹H NMR (CDCl₃, 600 MHz) δ 7.45-7.47(m, 3H), 7.12-7.17 (m, 4H), 6.98 (t, J=8.4 Hz, 1H), 6.12 (s, 1H), 5.16(s, 1H), 3.18 (d, J=15 Hz, 1H), 2.75 (d, J=15 Hz, 11), 2.65-2.70 (m,2H), 2.41 (m, 1H), 2.28 (d, J=15 Hz, 1H), 1.59-1.83 (m, 5H), 1.26 (s,3H), 1.24 (t, J=7.8 Hz, 3H).

Example 208

Step 1

Example 38 (11.6 mg, 0.03 mmol) was dissolved in EtOAc (2 mL) and NaH(10 mg, 0.42 mmol) was added. The reaction was stirred at roomtemperature for 5 minutes and then MeI (3 μL, 0.05 mmol) was added.After 15 minutes, the reaction was poured into water (10 mL) andextracted with EtOAc (25 mL). The organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby preparatory thin layer chromatography (5% MeOH/CH₂Cl₂) to afford 10.0mg (83%) of Example 208. R_(f)=0.18 (5% MeOH/CH₂Cl₂). LCMS=404; (M+1)⁺.¹H NMR (CDCl₃, 500 MHz) δ 8.59 (bs, 21), 7.44-7.47 (m, 3H), 7.21 (d,J=4.0 Hz, 2H), 7.15 (t, J=8.5 Hz, 2H), 6.11 (d, J=1.5 Hz, 1H), 4.48 (s,1H), 3.28 (s, 3H), 3.17 (d, J=15 Hz, 1H), 2.75 (d, J=15 Hz, 1H), 2.38(m, 1H), 2.25 (d, J=14.5 Hz, 1H), 1.68-1.79 (m, 2H), 1.48-1.57 (m, 2H),1.18 (s, 3H), 1.10 (m, 1H).

The following compound was synthesized starting from Example 32 andfollowing a procedure analogous to that described for Examples 208:

LCMS Compound Molecular structure (M + 1)⁺ 209

421

Example 210

Step 1

Example 81 (9.0 mg, 0.019 mmol) was dissolved in CH₂Cl₂ (1 mL) and thesolution was cooled to −40° C. m-CPBA (6.4 mg, 0.037 mmol) was added andthe reaction was stirred at 40° C. for 20 minutes. The reaction was thendiluted with EtOAc (25 mL), washed with saturated aq. NaHSO₃, saturatedNaHCO₃, and brine (10 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flashchromatography (100% EtOAc to 5% MeOH/EtOAc) to afford 7.2 mg (78%) ofExample 210. R_(f)=0.19 (EtOAc). LCMS=499; (M+1)⁺. ¹H NMR (CDCl₃, 600MHz) δ 7.43-7.46 (m, 3H), 7.26 (m, 1H), 7.14-7.16 (m, 2H), 7.08 (dd,J=8.4, 10.0 Hz, 1H), 6.97 (m, 1H), 6.11 (d, J=2.4 Hz, 1H), 5.12 (s, 1H),5.05 (dd, J=10.2, 3.0 Hz, 1H), 4.97 (dd, J=10.2, 8.4 Hz, 1H), 3.16 (d,J=15 Hz, 1H), 2.73 (d, J=15 Hz, 1H), 2.72 (s, 3H), 2.26-2.42 (m, 2H),1.64-1.83 (m, 3H), 1.51 (m, 1H), 1.24 (s, 3H), 1.18 (m, 1H).

Example 211

Step 1

Example 81 (6.0 mg, 0.012 mmol) was dissolved in THF (100 μL) and MeOH(400 μL) was added. The solution was cooled to 0° C. Oxone (14 mg, 0.024mmol) was dissolved in H₂O (400 μL) and this solution was added to thesolution of 81. The reaction was warmed to room temperature and stirredfor 4 hours. The reaction was then diluted with EtOAc (25 mL) and washedwith water, saturated aq. NaHSO₃, saturated NaHCO₃, and brine (10 mLeach). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by preparatory thin layerchromatography (60% EtOAc/hexanes) to afford 1.6 mg (25%) of Example211. R_(f)=0.54 (75% EtOAc/hexanes). LCMS=515; (M+1)⁺. ¹H NMR (CDCl₃,500 MHz) δ 7.45-7.48 (m, 3H), 7.01-7.26 (m, 4H), 7.02 (m, 1H), 6.12 (d,J=2.0 Hz, 1H), 5.16 (s, 1H), 5.02 (s, 3H), 3.18 (d, J=15.5 Hz, 1H), 3.07(s, 3H), 2.74 (d, J=15 Hz, 1H), 2.40 (m, 1H), 2.28 (m, 1H), 1.52-1.89(m, 4H), 1.25 (s, 3H), 1.19 (m, 1H).

Example 212

Step 1

Example 119 (11.0 mg, 0.026 mmol) was dissolved in THF (200 μL) and MeOH(200 μL) was added. The solution was cooled to 0° C. Oxone (32 mg, 0.051mmol) was dissolved in H₂O (800 μL) and this solution was added to thesolution of 119. The reaction was warmed to room temperature and stirredfor 4 hours. At this point, additional oxone (32 mg, 0.051 mmol) wasadded as a solid. The reaction was stirred at room temperature for anadditional 24 hours and then diluted with EtOAc (25 mL) and washed withwater, saturated NaHCO₃, and brine (10 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby preparatory thin layer chromatography (60% EtOAc/hexanes) to afford2.5 mg (21%) of Example 212. R_(f)=0.13 (40% EtOAc/hexanes). LCMS=463;(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.76 (d, J=7.5 Hz, 1H), 7.52-7.60 (m,3H), 7.40-7.45 (m, 3H), 7.14 (t, J=8.5 Hz, 21), 6.72 (s, 1H), 6.14 (s,1H), 5.02 (d, J=2.0 Hz, 1H), 2.89 (d, J=14.5 Hz, 1H), 2.65 (m, 1H), 2.55(d, J=15 Hz, 1H), 2.37-2.45 (m, 2H), 2.28 (m, 1H), 1.96-2.14 (m, 3H),1.14 (s, 3H).

Example 213

Example 213 was prepared in the same manner as example 212, startingfrom example 120.

Biological Assays

The activity of the compounds of the present invention as modulators ofthe glucocorticoid receptor can be evaluated using the following assays:

Ligand Binding Assays

For the hGRα ligand binding assay, cytosols were prepared fromrecombinant baculovirus expressed receptors. Frozen cell pellets weredounce homogenized in ice cold KPO₄ buffer (10 mM KPO₄, 20 mM sodiummolybdate, 1 mM EDTA, 5 mM DTT and complete protease inhibitor tabletsfrom Boehringer Mannheim) with a “B” plunger. The homogenates werecentrifuged at 35,000×g for 1 h at 4° C. in a JA-20 rotor. The IC_(50s)were determined by incubating the cytosols at a final concentration of2.5 nM [1,2,4,6,7-³H] Dexamethasone in the presence of increasingconcentrations (10-11 to 10-6) of cold dexamethasone or the ligands at4° C. for 24 h. Bound and free were separated by a gel filtration assay,(Geissler et al, personal communication). Half of the reaction was addedto a gel filtration plate (MILLIPORE) containing sephadex G-25 beadsthat was previously equilibrated with KPO4 buffer containing 1 mg/ml BSAand centrifuged at 1000×g for 5 min. The reaction plate was centrifugedat 1000×g for 5 min. and the reactions were collected in a second96-well plate and scintillation cocktail was added and counted in(Wallac) double coincidence beta counter. The IC_(50s) were calculatedusing a 4-parameter fit program.

Compounds of the invention demonstrated an activity in the range of 0.1nM to 1 μM in the assay procedure described above.

1. A compound which is:

or a pharmaceutically acceptable salt thereof.
 2. A compound selectedfrom the following group:

or a pharmaceutically acceptable salt of any of the foregoing compounds.